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  • 1. Broom, Oliver Jay
    et al.
    Zhang, Yuan
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    Massoumi, Ramin
    Sjölander, Anita
    CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.2009In: PloS one, ISSN 1932-6203, Vol. 4, no 7, p. e6371-Article in journal (Refereed)
    Abstract [en]

    Increased epithelial cell expression of the cyclooxygenase-2 (COX-2) enzyme is a characteristic event of both inflammatory bowel disease and colon cancer. We here report the novel findings that collagen I-induced de novo synthesis of COX-2 in intestinal epithelial cells is inhibited by pertussis toxin (PTX) and by an inhibitory peptide selective for the heterotrimeric G alpha(i3)-protein. These findings could be explained by a regulatory involvement of the G-protein-dependent integrin-associated protein CD47. In support of this notion, we observed a collagen I-induced association between CD47 and alpha2 integrins. This association was reduced by a blocking anti-CD47 antibody but not by PTX or a control anti-beta2 antibody. Furthermore, a blocking antibody against CD47, dominant negative CD47 or specific siRNA knock down of CD47, significantly reduced collagen I-induced COX-2 expression. COX-2 has previously been shown to regulate intestinal epithelial cell adhesion and migration. Morphological analysis of intestinal cells adhering to collagen I revealed a co-localisation of CD47 and alpha2 integrins to non-apoptotic membrane blebs enriched in Rho A and F-actin. The blocking CD47 antibody, PTX and a selective COX-2 inhibitor, dramatically inhibited the formation of these blebs. In accordance, migration of these cells on a collagen I-coated surface or through a collagen I gel were significantly reduced by the CD47 blocking antibody, siRNA knock down of CD47 and the COX-2 inhibitor NS-398. In conclusion, we present novel data that identifies the G-protein-dependent CD47 protein as a key regulator of collagen I-induced COX-2 expression and a promoter of intestinal epithelial cell migration.

  • 2. Bruce, Lesley J
    et al.
    Ghosh, Sandip
    King, May Jean
    Layton, D Mark
    Mawby, William J
    Stewart, Gordon W
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Delaunay, Jean
    Tanner, Michael J A
    Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, no 5, p. 1878-1885Article in journal (Refereed)
    Abstract [en]

    We present data on a patient of South Asian origin with recessive hereditary spherocytosis (HS) due to absence of protein 4.2 [4.2 (-) HS]. Protein 4.2 cDNA sequence analysis showed the presence of a novel 41-bp frameshift deletion that predicts a truncated peptide designated protein 4.2 Hammersmith. Quantitative reverse transcription-polymerase chain reaction indicated that the mutant mRNA was unstable. Sequencing of protein 4.2 genomic DNA revealed that the deletion stems from aberrant splicing. The proband was homozygous for a G>T substitution at position 1747 (cDNA numbering) that activates a cryptic acceptor splice site within exon 11 of the protein 4.2 gene (EPB42). The proband's mother was found to be heterozygous for this substitution. Unlike protein 4.2 null mice, the proband's red cells showed no evidence for abnormal cation permeability. Quantitation of red cell membrane proteins was carried out by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting, and flow cytometric measurement. CD47, a protein associated with the Rh complex, was markedly reduced to about 1% (in the proband) and 65% (in the mother) that found in healthy controls. The Rh-associated glycoprotein migrated with a higher than normal apparent molecular weight on SDS-PAGE. There was no obvious reduction in Rh polypeptides. These observations indicate that protein 4.2 and CD47 interact in the human red cell membrane. They provide further evidence for an association between the band 3 complex (band 3, ankyrin, protein 4.2, glycophorin A) and the Rh complex (Rh-associated glycoprotein, Rh polypeptides, glycophorin B, CD47, LW) and define a point of attachment between the Rh complex and the red cell cytoskeleton.

  • 3.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47045-Article in journal (Refereed)
    Abstract [en]

    High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2(+)) or M2 (CD163(+)) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2(+) and CD163(+) cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.

  • 4.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Macrophages: Good guys in colorectal cancer2013In: Oncoimmunology, ISSN 2162-4011, Vol. 2, no 2, p. e23038-Article in journal (Refereed)
    Abstract [en]

    Macrophages play a complex role in tumor progression since they can exert both tumor-preventing (M1 macrophages) and tumor-promoting (M2 macrophages) activities. In colorectal carcinoma (CRC), at odds to many other cancers, macrophage infiltration has been correlated with an improved patient survival. In a recent study, we have evaluated the distribution of M1 and M2 macrophage subtypes in CRC and their impact on patient prognosis.

  • 5.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74982-Article in journal (Refereed)
    Abstract [en]

    Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.

  • 6.
    Fossati-Jimack, Liliane
    et al.
    University of Geneva.
    Azeredo da Silveira, Samareh
    University of Geneva.
    Moll, Thomas
    University of Geneva.
    Kina, Tatsuo
    Kyoto University.
    Kuypers, Frans A
    Children's Hospital Oakland Research Institute, Oakland, California.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Reininger, Luc
    Institut National de la Santé et de la Recherche Médicale U 399, Marseille.
    Izui, Shozo
    University of Geneva.
    Selective increase of autoimmune epitope expression on aged erythrocytes in mice: implications in anti-erythrocyte autoimmune responses2002In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 18, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of changes occurring during red blood cell (RBC) ageing on the RBC-binding activity of pathogenic anti-erythrocyte monoclonal antibodies derived from autoimmune-prone New Zealand black (NZB) mice. As assessed by flow cytometric analysis on in vivo biotinylated RBCs, all five NZB-derived anti-RBC mAb exhibited more efficient binding to aged RBCs than to young RBCs, and resulted in a selective elimination of more aged RBCs from the circulating blood. In addition, treatment of RBCs with proteases markedly enhanced the binding of all five anti-RBC mAb, raising the possibility that increased exposure of autoimmune epitopes on aged RBCs may be in part, a result of contacts with proteolytic enzymes during the lifetime of circulating RBCs. In marked contrast, the binding activity of mAb raised in non-autoimmune animals against antigens expressed on RBCs, such as CD44, CD47, CD147 and TER-119, was either decreased or unchanged with RBC ageing, and these epitopes, except for that recognized by anti-CD47 mAb, were highly sensitive to mild treatment with proteases. Our data unravel the unique molecular feature of RBC epitopes involved in autoimmune haemolytic anaemia, suggesting that membrane alterations in aged RBCs might play a significant role in the development of the autoantibody response to RBCs.

  • 7. Gardai, Shyra J
    et al.
    McPhillips, Kathleen A
    Frasch, S Courtney
    Janssen, William J
    Starefeldt, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Murphy-Ullrich, Joanne E
    Bratton, Donna L
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Michalak, Marek
    Henson, Peter M
    Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte2005In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 123, no 2, p. 321-334Article in journal (Refereed)
    Abstract [en]

    Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

  • 8.
    Gitik, Miri
    et al.
    Hebrew University Hadassah Medical School, Jerusalem.
    Liraz Zaltsman, Sigal
    Hebrew University Hadassah Medical School, Jerusalem.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Reichert, Fanny
    Hebrew University Hadassah Medical School, Jerusalem.
    Rotshenker, Shlomo
    Hebrew University Hadassah Medical School, Jerusalem.
    Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPalpha (signal regulatory protein-alpha) on phagocytes2011In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 8, no 1, p. 24-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Traumatic injury to axons produces breakdown of axons and myelin at the site of the lesion and then further distal to this where Wallerian degeneration develops. The rapid removal of degenerated myelin by phagocytosis is advantageous for repair since molecules in myelin impede regeneration of severed axons. Thus, revealing mechanisms that regulate myelin phagocytosis by macrophages and microglia is important. We hypothesize that myelin regulates its own phagocytosis by simultaneous activation and down-regulation of microglial and macrophage responses. Activation follows myelin binding to receptors that mediate its phagocytosis (e.g. complement receptor-3), which has been previously studied. Down-regulation, which we test here, follows binding of myelin CD47 to the immune inhibitory receptor SIRPalpha (signal regulatory protein-alpha) on macrophages and microglia.

    METHODS: CD47 and SIRPalpha expression was studied by confocal immunofluorescence microscopy, and myelin phagocytosis by ELISA.

    RESULTS: We first document that myelin, oligodendrocytes and Schwann cells express CD47 without SIRPalpha and further confirm that microglia and macrophages express both CD47 and SIRPalpha. Thus, CD47 on myelin can bind to and subsequently activate SIRPalpha on phagocytes, a prerequisite for CD47/SIRPalpha-dependent down-regulation of CD47+/+ myelin phagocytosis by itself. We then demonstrate that phagocytosis of CD47+/+ myelin is augmented when binding between myelin CD47 and SIRPalpha on phagocytes is blocked by mAbs against CD47 and SIRPalpha, indicating that down-regulation of phagocytosis indeed depends on CD47-SIRPalpha binding. Further, phagocytosis in serum-free medium of CD47+/+ myelin is augmented after knocking down SIRPalpha levels (SIRPalpha-KD) in phagocytes by lentiviral infection with SIRPalpha-shRNA, whereas phagocytosis of myelin that lacks CD47 (CD47-/-) is not. Thus, myelin CD47 produces SIRPalpha-dependent down-regulation of CD47+/+ myelin phagocytosis in phagocytes. Unexpectedly, phagocytosis of CD47-/- myelin by SIRPalpha-KD phagocytes, which is not altered from normal when tested in serum-free medium, is augmented when serum is present. Therefore, both myelin CD47 and serum may each promote SIRPalpha-dependent down-regulation of myelin phagocytosis irrespective of the other.

    CONCLUSIONS: Myelin down-regulates its own phagocytosis through CD47-SIRPalpha interactions. It may further be argued that CD47 functions normally as a marker of "self" that helps protect intact myelin and myelin-forming oligodendrocytes and Schwann cells from activated microglia and macrophages. However, the very same mechanism that impedes phagocytosis may turn disadvantageous when rapid clearance of degenerated myelin is helpful.

  • 9.
    Hagnerud, Sven
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Manna, Partha Pratim
    Cella, Marina
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Frazier, William A
    Colonna, Marco
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Deficit of CD47 results in a defect of marginal zone dendritic cells, blunted immune response to particulate antigen and impairment of skin dendritic cell migration.2006In: Journal of Immunology, ISSN 0022-1767, Vol. 176, no 10, p. 5772-8Article in journal (Refereed)
    Abstract [en]

    CD47 is a ubiquitously expressed cell surface glycoprotein that associates with integrins and regulates chemotaxis, migration, and activation of leukocytes. CD47 is also a ligand for signal regulatory protein alpha, a cell surface receptor expressed on monocytes, macrophages, granulocytes, and dendritic cell (DC) subsets that regulates cell activation, adhesion, and migration. Although the function of CD47 in macrophages and granulocytes has been studied in detail, little is known about the role of CD47 in DC biology in vivo. In this study we demonstrate that CD47(-/-) mice exhibit a selective reduction of splenic CD11c(high)CD11b(high)CD8alpha(-)CD4(+) DCs. These DCs correspond to marginal zone DCs and express signal regulatory protein alpha, possibly explaining their selective deficiency in CD47(-/-) mice. Deficiency of marginal zone DCs resulted in impairment of IgG responses to corpusculate T cell-independent Ags. Although epidermal DCs were present in normal numbers in CD47(-/-) mice, their migration to draining lymph nodes in response to contact sensitization was impaired, while their maturation was intact. In vitro, CD47(-/-) mature DCs showed normal CCR7 expression but impaired migration to CCL-19, whereas immature DC response to CCL-5 was only slightly impaired. These results demonstrate a fundamental role of CD47 in DC migration in vivo and in vitro and in the function of marginal zone DCs.

  • 10.
    Hashemian, Sanaz Alsadat
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blocking cd47/ox101 makes the astrocytes permissive for nerve fiber growth2011In: Glia: 10th European meeting on Glial Cells in Health and Disease, New York, N.Y.: Wiley-Liss, Inc. , 2011, Vol. 59, p. S105-S106Conference paper (Refereed)
    Abstract [en]

    Crosstalk between astroglia and nerve fiber outgrowth might be an underlying mechanism for regeneration of nerve fibers and can be used in treatment of neurodegenerative diseases. This crosstalk might occur through the integrin-associated protein (CD47 in mouse or OX101 in rat), which serves as a ligand for signal regulatory protein-α (Sirpα) (P84/SHPS-1 in mouse or OX41 in rat), and as a receptor for thrombospondin (TSP). In the present study the localization of OX101 was assessed in organotypic tissue cultures from ventral mesencephalon (VM) of embryonic day (E) 14 rat fetuses, and its presence in astrocytes was observed. Thereafter, the effect of OX101 was blocked in E14 VM cultures by treatment with OX101 antibodies. A robust tyrosine hydroxylase (TH)- positive nerve fiber outgrowth was observed using immuohistochemistry. In addition, the neurons had migrated from the tissue slice. This result was in parallel with results achieved from E14 cultures of CD47 knockout mice, in which TH–positive nerve fiber growth was robust and independent of the presence of astrocytes, whilst in wildtype cultures nerve fibers were restricted to the astrocytes. Thus, these data demonstrate that CD47/OX101 can be an important molecule, which normally is produced by astrocytes and in its absence, the astrocytes become more permissive for nerve fiber growth.

  • 11.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.

  • 12.
    Holm, Cecilia Koskinen
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Engman, Sara
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation2016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, no 1, p. 268-273Article in journal (Refereed)
    Abstract [en]

    Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRP alpha) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRP alpha mutant mice lacking the cytoplasmic signaling domain of SIRPa. An impaired osteoblastogenesis in SIRP alpha-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPa-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRP alpha-mutant cells. In conclusion, our data suggest that SIRPa signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells. 

  • 13.
    Hult, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Transfusion of cryopreserved human red blood cells into healthy humans is associated with rapid extravascular hemolysis without a proinflammatory cytokine response2013In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 53, no 1, p. 28-33Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transfusion of stored red blood cells (RBCs) can be associated with adverse side effects. Recent studies in mice transfused with stored RBCs showed that a strong proinflammatory cytokine storm was induced due to extravascular hemolysis already at 2 hours after transfusion. Therefore, we here investigated if transfusion of 2 units of cryopreserved autologous RBCs induced a proinflammatory response in healthy human volunteers.

    STUDY DESIGN AND METHODS: Two units of autologous RBCs, cryopreserved for 16 weeks, were transfused into 10 healthy human volunteers. Serum and blood samples taken at 2 hours before and at 2 and 48 hours after transfusion were analyzed for signs of extravascular hemolysis and the presence of proinflammatory cytokines.

    RESULTS: At 2 hours after transfusion, transferin-bound serum iron, as well as transferin saturation and total bilirubin, were already significantly increased. These measures all returned back toward that in pretransfusion samples at 48 hours after transfusion. No increases in the production of the proinflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, monocyte chemotactic protein-1, macrophage inflammatory protein-1β, or tumor necrosis factor-α were detected at any time point after transfusion.

    CONCLUSION: Although a significant level of extravascular hemolysis already occurred at 2 hours after transfusion of cryopreserved RBCs, there were no signs of proinflammatory cytokine production up to 48 hours after transfusion.

  • 14.
    Hult, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Toss, Fredrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Phagocytosis of liquid-stored red blood cells in vitro requires serum and macrophage scavenger receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: Red blood cells (RBCs) undergo structural and metabolic changes with prolonged storage, which ultimately may decrease their survival after transfusion. Although the storage-induced damage to RBCs has been rather well described biochemically, little is known about the mechanisms underlying the recognition and rapid clearance of the damaged cells by macrophages.STUDY DESIGN AND METHODS: We here used a murine model for cold (+4°C) RBC storage and transfusion. Phagocytosis of human or murine RBCs, liquid stored for 6-8 weeks or 10-14 days respectively, was investigated in murine peritoneal macrophages.RESULTS: The effects of storage on murine RBCs resembled that described for stored human RBCs with regard to decreased adenosine triphosphate (ATP) levels, accumulation of microparticles during storage, and RBC recovery kinetics after transfusion. Under serum-free conditions, phagocytosis of stored human or murine RBCs was reduced by 70-75%, as compared with that in the presence of heat-inactivated fetal calf serum (FCS). Human serum promoted phagocytosis of stored human RBCs similar to that seen with FCS. By blocking macrophage class A scavenger receptors with fucoidan or dextran sulphate, phagocytosis of human or murine RBCs was reduced by more than 90%. Phagocytosis of stored human RBCs was also sensitive to inhibition by the phosphatidylinositol 3 kinase-inhibitor LY294002, the ERK1/2-inhibitor PD98059, or the p38 MAPK-inhibitor SB203580.CONCLUSIONS: RBCs damaged during liquid storage may be recognized by macrophage class A scavenger receptors and serum-dependent mechanisms. This species-independent recognition mechanism may help to further understand the rapid clearance of stored RBCs shortly after transfusion.

  • 15. Ikeda, Hiroshi
    et al.
    Okazawa, Hideki
    Ohnishi, Hiroshi
    Murata, Yoji
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Matozaki, Takashi
    Mutational analysis of the mechanism of negative regulation by SRC homology 2 domain-containing protein tyrosine phosphatase substrate-1 of phagocytosis in macrophages.2006In: Journal of Immunology, ISSN 0022-1767, Vol. 177, no 5, p. 3123-32Article in journal (Refereed)
    Abstract [en]

    Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) is a transmembrane protein predominantly expressed in macrophages. The binding of CD47 on RBCs to SHPS-1 on macrophages is implicated in inhibition of phagocytosis of the former cells by the latter. We have now shown that forced expression in mouse RAW264.7 macrophages of a mutant version (SHPS-1-4F) of mouse SHPS-1, in which four tyrosine phosphorylation sites are replaced by phenylalanine, markedly promoted Fc gammaR-mediated phagocytosis of mouse RBCs or SRBCs. Forced expression of another mutant form (SHPS-1-deltaCyto) of mouse SHPS-1, which lacks most of the cytoplasmic region, did not promote such phagocytosis. Similarly, forced expression of a rat version of SHPS-1-4F, but not that of rat wild-type SHPS-1 or SHPS-1-deltaCyto, in RAW264.7 cells enhanced Fc gammaR-mediated phagocytosis of RBCs. Tyrosine phosphorylation of endogenous SHPS-1 as well as its association with Src homology 2 domain-containing protein tyrosine phosphatase-1 were not markedly inhibited by expression of SHPS-1-4F. Furthermore, the attachment of IgG-opsonized RBCs to RAW264.7 cells was markedly increased by expression of SHPS-1-4F, and this effect did not appear to be mediated by the interaction between CD47 and SHPS-1. These data suggest that inhibition by SHPS-1 of phagocytosis in macrophages is mediated, at least in part, in a manner independent of the transinteraction between CD47 and SHPS-1. In addition, the cytoplasmic region as well as tyrosine phosphorylation sites in this region of SHPS-1 appear indispensable for this inhibitory action of SHPS-1. Moreover, SHPS-1 may regulate the attachment of RBCs to macrophages by an as yet unidentified mechanism.

  • 16.
    Ishikawa-Sekigami, Tomomi
    et al.
    Gunma University.
    Kaneko, Yoriaki
    Gunma University.
    Saito, Yasuyuki
    Gunma University.
    Murata, Yoji
    Gunma University.
    Okazawa, Hideki
    Gunma University.
    Ohnishi, Hiroshi
    Gunma University.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Nojima, Yoshihisa
    Gunma University.
    Matozaki, Takashi
    Gunma University.
    Enhanced phagocytosis of CD47-deficient red blood cells by splenic macrophages requires SHPS-1.2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 343, no 4, p. 1197-200Article in journal (Refereed)
    Abstract [en]

    The interaction of CD47 on red blood cells (RBCs) with SHPS-1 on macrophages is implicated to prevent the phagocytosis of the former cells by the latter cells. Indeed, the rate of clearance of transfused CD47-deficient (CD47(-/-)) RBCs from the bloodstream of wild-type mice was markedly increased compared with wild-type RBCs. Conversely, the rate of clearance of transfused wild-type RBCs was markedly increased in mice that expressed a mutant form of SHPS-1 lacking most of the cytoplasmic region of the protein. However, we here found that the clearance of CD47(-/-) RBCs in SHPS-1 mutant mice was minimal. In addition, the phagocytosis of CD47(-/-) RBCs by splenic macrophages from SHPS-1 mutant mice was markedly reduced compared with wild-type macrophages. These results thus suggest an additional role for CD47 on RBCs in the negative regulation of phagocytosis by macrophages and in determination of the life span of circulating RBCs.

  • 17.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boman, Andreas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan..
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 460, no 3, p. 645-650Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein α (SIRPα) is an immunoglobulin super family protein predominantly expressed by myeloid but not lymphoid cells, and its role in lymphocyte homeostasis and function is still to be revealed. We demonstrate that mice bearing a mutant SIRPα lacking the cytoplasmic signaling domain (SIRPα MT) had an increased amount of splenic marginal zone (MZ) B cells compared to wild-type controls. Immunohistochemical analysis revealed an increased localization of MZB cells into B cell follicular areas of the white pulp in SIRPα MT spleens. However, we found no signs of an increased MZB cell activation level in MT mice. The immune response to T-independent antigens in vivo was slightly increased in SIRPα MT mice while sorted MZB from these mice responded normally to LPS in vitro. Bone marrow reconstitution experiments demonstrated that the MZB cell phenotype of SIRPα MT mice was due to lack of SIRPα signaling in non-hematopoietic cells. In contrast, MZ retention of MZ macrophages required hematopoietic SIRPα, while normal distribution of metallophilic macrophages required non-hematopoietic SIRPα signaling. In summary, these data identified SIRPα signaling in non-hematopoietic cells to play an important role in regulating the numbers and positioning MZB cell in the spleen.

  • 18.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe, Japan.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen2015In: PLoS One, Vol. 10, no 7, article id e0134113Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.

  • 19.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Engman, Sara
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Reduced SIRPα phosphorylation and concommitant SHP-2–PI3K–Akt2 signaling decrease osteoblast differentiationArticle in journal (Other academic)
    Abstract [en]

    Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on an intricate cellular signaling including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRPα) are suggested to regulate bone cell differentiation. In the present study, we investigated osteoblastic differentiation of bone marrow stromal cells from SIRPα mutant mice lacking the cytoplasmic signaling domain of SIRPα. Moreover, we compared downstream signaling events of SIRPα in wild-type and CD47-deficient mouse bone marrow stromal cells. SIRPα-mutant stromal cells showed significantly less expression of Runx2, Sp7 (osterix), Bglap (osteocalcin), and Akp1 (alkaline phosphatase) mRNA compared to stromal cells from wild-type mice. An impaired osteoblastogenesis in SIRPα-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. Western blot analyses showed that CD47 expression was required for Src homology-2 domain containing protein tyrosine phosphatase- 2 (SHP-2) to associate with SIRPa. As a result, SHP-2 and Akt2 in stromal cells from CD47 deficient mice were less phosphorylated, as compared to that in wild-type stromal cells. In conclusion, we here show that CD47-dependent SIRPα signaling through SHP-2–PI3K–Akt2 strongly influences osteogenic differentiation of bone marrow stromal cells.

  • 20.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Persson, Emelie
    Umeå University, Faculty of Medicine, Department of Odontology.
    Baldock, Paul
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Boström, Ingrid
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein α (SIRPα) signaling2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 41, p. 29333-29344Article in journal (Refereed)
    Abstract [en]

    Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1α,25(OH)2-vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor κβ ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast-associated genes osterix, Alp/Akp1, and α-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPα (signal regulatory protein α), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPα cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPα mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47-induced SIRPα signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPα-dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts.

  • 21.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Baldock, P.
    Garvan Institute of Medical Research, Darlinghurst, New South Wales.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lack of CD47 leads to impaired bone cell differentiation and results in an osteopenic bone phenotype2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S42-S43Article in journal (Refereed)
  • 22.
    Larsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hult, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Nilsson, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Olsson, Mattias
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Red blood cells with elevated cytoplasmic Ca2+ are primarily taken up by splenic marginal zone macrophages and CD207+dendritic cells2016In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 56, no 7, p. 1834-1844Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The normal red blood cell (RBC) life span may be significantly reduced when RBCs are stored under blood bank conditions, resulting in a reduced 24-hour survival after transfusion. The damage of stored RBCs is probably multifactorial as stored RBCs share features of both senescence and suicidal RBC death (eryptosis). Since an increased intracellular Ca2+ concentration ([Ca2+](i)) is one key feature of eryptosis, we here investigated if stored human RBCs had increased [Ca2+](i) and the mechanisms behind uptake of such RBCs in a murine model.

    STUDY DESIGN AND METHODS: The intracellular Ca2+ content of RBCs was determined using the Ca2+ probe Fluo-3 and flow cytometry. In vivo uptake of Ca2+ ionophore-treated murine RBCs (Ca2+-RBCs) was investigated in recipient mice, using flow cytometry and immunohistochemical analysis.

    RESULTS: A small fraction of human RBCs accumulated [Ca2+](i) during storage for up to 42 days under blood bank conditions. In a murine model, where fresh or Ca2+-RBCs were transfused, Ca2+-RBCs were mainly trapped by MARCO+ splenic marginal zone macrophages and CD11c+ CD207+ dendritic cells (DCs) within 1 hour after transfusion. In marked contrast, freshly transfused RBCs aging normally in circulation were cleared much slower and preferentially by F4/80+ red pulp macrophages. CD47 on the Ca2+-RBCs did not affect their clearance by splenic phagocytic cells.

    CONCLUSIONS: A small fraction of RBCs accumulate [Ca2+](i) during storage, and in a murine model such RBCs are recognized by splenic macrophages and DCs in ways similar to what has been reported for nucleated apoptotic cells.

  • 23.
    Larsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hult, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Nilsson, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Olsson, Mattias
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Splenic uptake of RBCs with an elevated cytoplasmic Ca2+-concentration primarily involves marginal zone macrophages and CD207+ dendritic cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Normally senescent red blood cells (RBCs) have a rather fixed life-span after which they are eliminated from the circulation mainly by macrophages in the spleen and liver. However, the normal life-span may be significantly reduced when RBCs are stored under blood bank conditions, which ultimately results in a reduced 24 hour survival after transfusion. Although not completely understood, the damage occurring to some of the stored RBCs is probably multifactorial as stored RBCs shares features of both senescence and suicidal RBC death (eryptosis). One key cellular event associated with eryptosis is an increased intracellular Ca2+-concentration. We found that human RBCs stored for up to 42 days under blood bank conditions contained a small subset of cells with an increased intracellular Ca2+-concentration corresponding to that during eryptosis. Since little is known about the mechanisms mediating uptake and clearance of eryptotic RBCs in vivo, we further investigated this using a murine transfusion model of Ca2+ ionophore-treated RBCs (Ca2+-RBCs). Ca2+-RBCs were mainly trapped by MARCO+ splenic marginal zone macrophages and CD11c+ dendritic cells (DCs) already at 1 hour after transfusion. Among DCs, CD11c+ CD207+ DCs in the marginal zone were particularly efficient in mediating uptake of Ca2+-RBCs. Similar to that found in vitro, CD47 on the Ca2+-RBCs did not affect their clearance in vivo. Thus, RBCs with an increased intracellular Ca2+-concentration accumulates during RBC storage, and in a murine model such RBCs are recognized by splenic macrophages and DCs in ways similar to what has been reported for nucleated apoptotic cells.

  • 24.
    Lundberg, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Koskinen, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Baldock, Paul A
    Löthgren, Hanna
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Osteoclast formation is strongly reduced both in vivo and in vitro in the absence of CD47/SIRPalpha-interaction2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 2, p. 444-448Article in journal (Refereed)
    Abstract [en]

    Physical interaction between the cell surface receptors CD47 and signal regulatory protein alpha (SIRPalpha) was reported to regulate cell migration, phagocytosis, cytokine production, and macrophage fusion. However, it is unclear if the CD47/SIRPalpha-interaction can also regulate macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-stimulated formation of osteoclasts. Here, we show that functional blocking antibodies to either CD47 or SIRPalpha strongly reduced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)+ osteoclasts in cultures of murine hematopoietic cells, stimulated in vitro by M-CSF and RANKL. In addition, the numbers of osteoclasts formed in M-CSF/RANKL-stimulated bone marrow macrophage cultures from CD47-/- mice were strongly reduced, and bones of CD47-/- mice exhibited significantly reduced osteoclast numbers, as compared with wild-type controls. We conclude that the CD47/SIRPalpha interaction is important for M-CSF/RANKL-stimulated osteoclast formation both in vivo and in vitro, and that absence of CD47 results in decreased numbers of osteoclasts in CD47-/- mice.

  • 25. Manna, Partha P
    et al.
    Dimitry, Julie
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Frazier, William A
    CD47 augments Fas/CD95-mediated apoptosis.2005In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 280, no 33, p. 29637-44Article in journal (Refereed)
    Abstract [en]

    Fas (CD95) mediates apoptosis of many cell types, but the susceptibility of cells to killing by Fas ligand and anti-Fas antibodies is highly variable. Jurkat T cells lacking CD47 (integrin-associated protein) are relatively resistant to Fas-mediated death but are efficiently killed by Fas ligand or anti-Fas IgM (CH11) upon expression of CD47. Lack of CD47 impairs events downstream of Fas activation including caspase activation, poly-(ADP-ribose) polymerase cleavage, cytochrome c release from mitochondria, loss of mitochondrial membrane potential, and DNA cleavage. Neither CD47 signaling nor raft association of CD47 is required to enable Fas apoptosis. CH11 induces association of Fas and CD47. Primary T cells from CD47-null mice are also protected from Fas-mediated killing relative to wild type T cells. Thus CD47 associates with Fas upon its activation and augments Fas-mediated apoptosis.

  • 26.
    Marschinke, Franziska
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Hashemian, Sanaz Alsadat
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Matozaki, Takashi
    Kobe University Graduate School of Medicine.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    The absence of CD47 promotes nerve fiber growth from cultured ventral mesencephalic dopamine neurons2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e45218-Article in journal (Refereed)
    Abstract [en]

    In ventral mesencephalic organotypic tissue cultures, two timely separated sequences of nerve fiber growth have been observed. The first appearing nerve fiber pattern is a long-distance outgrowth that occurs before astrocytes start to proliferate and migrate to form an astrocytic monolayer that finally surrounds the tissue slice. These long-distance growing nerve fibers are retracted as the astrocytes migrate, and are followed by a secondary outgrowth. The secondary outgrowth is persistent in time but reaches short distances, comparable with outgrowth seen from a dopaminergic graft implanted to the brain. The present study was focused on the interaction between the astrocytes and the long-distance growing non-glial associated nerve fibers. Cross talk between astroglia and neurite formation might occur through the integrin-associated protein CD47. CD47 serves as a ligand for signal regulatory protein (SIRP) alpha and as a receptor for the extracellular matrix protein thrombospondin-1 (TSP-1). Embryonic day 14 ventral mesencephalic tissue from CD47(+/+) and CD47(-/-) mice was used to investigate astrocytic migration and the tyrosine hydroxylase (TH) -positive outgrowth that occurred remote from the astrocytes. TH-immunohistochemistry demonstrated that the non-glial-associated nerve fiber outgrowth in CD47(-/-) cultures reached significantly longer distances and higher density compared to nerve fibers formed in CD47(+/+) cultures at 14 days in vitro. These nerve fibers often had a dotted appearance in CD47(+/+) cultures. No difference in the astrocytic migration was observed. Further investigations revealed that the presence of CD47 in control culture did neither hamper non-glial-associated growth through SIRP alpha nor through TSP-1 since similar outgrowth was found in SIRP alpha mutant cultures and in CD47(+/+) cultures treated with blocking antibodies against the TSP-1, respectively, as in the control cultures. In conclusion, long-distance growing nerve fiber formation is promoted by the absence of CD47, even though the presence of astrocytes is not inhibited.

  • 27.
    Marschinke, Franziska
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Strömberg, Ingrid
    CD47 - Sirpα interactions affects long-distance growing nerve fibers from cultured ventral mesencephalic dopamine neuronsManuscript (Other (popular science, discussion, etc.))
  • 28.
    Maruyama, Toshi
    et al.
    Gunma University, Gunma University Graduate School of Medicine.
    Kusakari, Shinya
    Gunma University.
    Sato-Hashimoto, Miho
    Gunma University.
    Hayashi, Yuriko
    Gunma University.
    Kotani, Takenori
    Gunma University.
    Murata, Yoji
    Kobe University Graduate School of Medicine.
    Okazawa, Hideki
    Kobe University Graduate School of Medicine.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Kishi, Shoji
    Gunma University Graduate School of Medicine.
    Matozaki, Takashi
    Kobe University Graduate School of Medicine, Gunma University,.
    Ohnishi, Hiroshi
    Hypothermia-induced tyrosine phosphorylation of SIRPα in the brain2012In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 121, no 6, p. 891-902Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein α (SIRPα) is a neuronal membrane protein that undergoes tyrosine phosphorylation in the brain of mice in response to forced swim (FS) stress in cold water, and this response is implicated in regulation of depression-like behavior in the FS test. We now show that subjection of mice to the FS in warm (37°C) water does not induce the tyrosine phosphorylation of SIRPα in the brain. The rectal temperature (T(rec) ) of mice was reduced to 27° to 30°C by performance of the FS for 10 min in cold water, whereas it was not affected by the same treatment in warm water. The level of tyrosine phosphorylation of SIRPα in the brain was increased by administration of ethanol or picrotoxin, starvation, or cooling after anesthesia, all of which also induced hypothermia. Furthermore, the tyrosine phosphorylation of SIRPα in cultured hippocampal neurons was induced by lowering the temperature of the culture medium. CD47, a ligand of SIRPα, as well as Src family kinases or SH2 domain-containing protein phosphatase 2 (Shp2), might be important for the basal and the hypothermia-induced tyrosine phosphorylation of SIRPα. Hypothermia is therefore likely an important determinant of both the behavioral immobility and tyrosine phosphorylation of SIRPα observed in the FS test.

  • 29. Meinderts, S. M.
    et al.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Beuger, B.
    Kuijpers, T. W.
    van den Berg, T. K.
    van Bruggen, R.
    Antibody-mediated phagocytosis of red blood cells by neutrophils in the human spleen2016In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 46, p. 77-77Article in journal (Other academic)
  • 30. Meinderts, Sanne M.
    et al.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Beuger, Boukje M.
    Klei, Thomas R. L.
    Johansson, Johanna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kuijpers, Taco W.
    Matozaki, Takashi
    Huisman, Elise J.
    De Haas, Masja
    Van den Berg, Timo K.
    Van Bruggen, Robin
    Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells2017In: Blood Advances, ISSN 2473-9529, Vol. 1, no 14, p. 875-886Article in journal (Refereed)
    Abstract [en]

    Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.

  • 31.
    Motegi, Sei-Ichiro
    et al.
    Gunma University.
    Okazawa, Hideki
    Gunma University.
    Murata, Yoji
    Gunma University.
    Kanazawa, Yoshitake
    Gunma University.
    Saito, Yasuyuki
    Gunma University.
    Kobayashi, Hisae
    Gunma University.
    Ohnishi, Hiroshi
    Gunma University.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Ishikawa, Osamu
    Gunma University.
    Matozaki, Takashi
    Gunma University.
    Essential roles of SHPS-1 in induction of contact hypersensitivity of skin.2008In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 121, no 1, p. 52-60Article in journal (Refereed)
    Abstract [en]

    SHPS-1 is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 and is abundant on the surface of CD11c(+) dendritic cells (DCs). We recently showed that SHPS-1 is essential for priming by DCs of CD4(+) T cells and for development of Th17 cell-mediated experimental autoimmunity. We have now further evaluated the importance of SHPS-1 and that of its ligand CD47 in contact hypersensitivity (CHS) to 2,4-dinitro-1-fluorobenzene (DNFB). Whereas the DNFB-induced CHS response was impaired in mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region, it was unaffected in CD47-deficient mice. Moreover, treatment of wild-type mice with mAbs to SHPS-1 that either block or do not block the binding of SHPS-1 to CD47 inhibited the CHS response. A mAb to CD47 had no such effect. The 2,4-dinitro-benzenesulfonic acid-induced proliferation of, and production of IFN-gamma or IL-17 by, T cells from DNFB-sensitized wild-type mice were inhibited by either mAb to SHPS-1 but not by that to CD47. In contrast, the blocking mAbs to SHPS-1, but not that to CD47, inhibited an allogeneic mixed leukocyte reaction. Both mAbs to SHPS-1, but not that to CD47, also inhibited the lipopolysaccharide- or polyinosinic-polycytidylic acid-induced production of TNF-alpha by DCs. These results suggest that SHPS-1 is essential for development of CHS, likely as a result of its positive regulation of the priming by DCs of CD4(+) T cells. However, such regulation by SHPS-1 does not appear to require its interaction with CD47.

  • 32. Murata, Takaaki
    et al.
    Ohnishi, Hiroshi
    Okazawa, Hideki
    Murata, Yoji
    Kusakari, Shinya
    Hayashi, Yuriko
    Miyashita, Motoaki
    Itoh, Hiroshi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Furuya, Nobuhiko
    Matozaki, Takashi
    CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42.2006In: Journal of Neuroscience, ISSN 1529-2401, Vol. 26, no 48, p. 12397-407Article in journal (Refereed)
    Abstract [en]

    The development of axons and dendrites is controlled by small GTP-binding proteins of the Rho family, but the upstream signaling mechanisms responsible for such regulation remain unclear. We have now investigated the role of the transmembrane protein cluster of differentiation 47 (CD47) in this process with hippocampal neurons. CD47-deficient neurons manifested markedly impaired development of dendrites and axons, whereas overexpression of CD47 promoted such development. Interaction of SH2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) with CD47 also induced the formation of dendritic filopodia and spines. These effects of CD47 were prevented by inhibition of either cell division cycle 42 (Cdc42) or Rac. In CD47-deficient neurons, autophosphorylation of Src was markedly reduced. In addition, overexpression of CD47 promoted the autophosphorylation of Src. Inhibition of Src family kinases indeed prevented CD47-promoted dendritic development. Inhibition of either FGD1-related Cdc42-guanine nucleotide exchange factor (GEF) (FRG) or Vav2, which is a GEF for Cdc42 and Rac and is activated by Src, also prevented the effects of CD47 on dendritic development. These results indicate that CD47 promotes development of dendrites and axons in hippocampal neurons in a manner dependent, at least in part, on activation of Cdc42 and Rac mediated by Src as well as by FRG and Vav2.

  • 33. Murata, Yoji
    et al.
    Tanaka, Daisuke
    Hazama, Daisuke
    Yanagita, Tadahiko
    Saito, Yasuyuki
    Kotani, Takenori
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Matozaki, Takashi
    Anti-human SIRP antibody is a new tool for cancer immunotherapy2018In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 109, no 5, p. 1300-1308Article in journal (Refereed)
    Abstract [en]

    Interaction of signal regulatory protein (SIRP) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRP enhanced both the Ab-dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) invitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic (NOD)/SCID mice. However, the effects of blocking Abs to human SIRP in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRP expressed on macrophages of immunodeficient mice. With the use of Rag2(c)(-/-)(-/-) mice harboring a transgene for human SIRP under the control of human regulatory elements (hSIRP-DKO mice), we here show that a blocking Ab to human SIRP significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti-human SIRP Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRP-DKO mice. Our results thus suggest that the combination of Abs to human SIRP with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRP-DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials.

  • 34.
    Nilsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Anders
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Olsson, Mattias
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Role of CD47 in regulating macrophage and dendritic cell uptake of calcium-induced experimentally senescent erythrocytes in vitro and in vivoManuscript (preprint) (Other academic)
    Abstract [en]

    During senescence, erythrocytes are rapidly eliminated by phagocytes in the spleen and liver,and the interplay between macrophages or dendritic cells (DCs) with lymphocytes in the spleen could be of importance to regulate self-tolerance and to prevent development of autoimmune hemolytic anemia (AIHA).The cell surface glycoprotein CD47 on the surface of host target cells can inhibit phagocytosis of normal circulating blood cells by binding to signal regulatory protein alpha (SIRPα) on macrophages and DCs. Here we investigated the clearance of Ca2+-ionophore-treated experimentally senescent erythrocytes (Ca2+-RBCs) in vivo, and if CD47 on Ca2+-RBCs regulated their uptake by macrophages in vitro or their clearance in vivo. Ca2+-RBCs exposed phosphatidylserine (PS) on their surface and were rapidly phagocytosed by macrophages in vitro. This uptake was dependent on heat-stable serum factors, but was not inhibited by CD47 on the erythrocytes. Following intravenous injection, a large fraction of PKH26-labeled Ca2+-RBCs were trapped by splenic marginal zone macrophages and DCs within 1 hour. In addition, at 20 hours after injection fluorescence from the injected cells could also be detected within the T cell area of the splenic white pulp and associated with both CD8+ and CD8- DCs. We found that DCs in wild-type (Wt) recipient mice showed equal uptake of transfused Wt and CD47-/- Ca2+-RBCs. DCs which had taken up Ca2+-RBCs showed a slight increase in expression levels of CD40, CD86 and MHC class II. In recipients of CD47-/- Ca2+-RBCs, DCs negative for RBC-uptake showed strongly increased expression of CD86, as compared with that in recipients of Wt Ca2+-RBCs. These findings suggest that PS+ erythrocytes may be recognized by splenic macrophages and DCs in ways similar to that reported for nucleated apoptotic cells. Uptake of senescent erythrocytes by DCs may serve as an important mechanism to maintain self-tolerance to erythrocyte antigens, and defects in this function may facilitate development of AIHA.

  • 35.
    Nilsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    CD47 promotes both phosphatidylserine-independent and phosphatidylserine-dependent phagocytosis of apoptotic murine thymocytes by non-activated macrophages2009In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 387, no 1, p. 58-63Article in journal (Refereed)
    Abstract [en]

    The ubiquitously expressed cell surface glycoprotein CD47 on host cells can inhibit phagocytosis of unopsonized or opsonized viable host target cells. Here we studied the role of target cell CD47 in macrophage uptake of viable or apoptotic murine thymocytes. As expected, IgG-opsonized viable CD47-/- thymocytes were taken up more efficiently than equally opsonized Wt thymocytes. However IgG-opsonized apoptotic thymocytes from Wt and CD47-/- mice were taken up equally. Although uptake of apoptotic thymocytes by non-activated bone marrow-derived macrophages was phosphatidylserine (PS)-independent, while uptake by non-activated resident peritoneal macrophages was PS-dependent, both macrophage populations showed a reduced uptake of non-opsonized apoptotic CD47-/- thymocytes, as compared with the uptake of apoptotic Wt thymocytes. This difference was only seen with non-activated macrophages, and not with β-1,3-glucan-activated macrophages. CD47 promoted binding of thymocytes to macrophages, which did not require F-actin polymerization. CD47 became clustered on apoptotic thymocytes, both colocalized with or separated from, clustered PS and cholesterol-rich GM-1 domains. Thus, CD47 does not inhibit, but rather support, both PS-independent and PS-dependent uptake of apoptotic cells in the murine system. This mechanism only comes into play in non-activated macrophages.

  • 36.
    Nilsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Vesterlund, Liselotte
    Karolinska Institute.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Macrophage expression of LRP1, a receptor for apoptotic cells and unopsonized erythrocytes, can be regulated by glucocorticoids2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 417, no 4, p. 1304-1309Article in journal (Refereed)
    Abstract [en]

    Macrophage phagocytosis of apoptotic cells, or unopsonized viable CD47(-/-) red blood cells, can be mediated by the interaction between calreticulin (CRT) on the target cell and LDL receptor-related protein-1 (LRP1/CD91/alpha 2-macroglobulin receptor) on the macrophage. Glucocorticoids (GC) are powerful in treatment of a range of inflammatory conditions, and were shown to enhance macrophage uptake of apoptotic cells. Here we investigated if the ability of GC to promote macrophage uptake of apoptotic cells could in part be mediated by an upregulation of macrophage LRP1 expression. Using both resident peritoneal and bone marrow-derived macrophages, we found that the GC dexamethasone could dose- and time-dependently increase macrophage LRP1 expression. The GC receptor-inhibitor RU486 could dose-dependently prevent LRP1 upregulation. Dexamethasone-treated macrophages did also show enhanced phagocytosis of apoptotic thymocytes as well as unopsonized viable CD47(-/-) red blood cells, which was sensitive to inhibition by the LRP1-agonist RAP. In conclusion, these data suggest that GC-stimulated macrophage uptake of apoptotic cells may involve an upregulation of macrophage LRP1 expression and enhanced LRP1-mediated phagocytosis. (C) 2012 Elsevier Inc. All rights reserved.

  • 37.
    Ohnishi, Hiroshi
    et al.
    Gunma University.
    Murata, Takaaki
    Gunma University, Gunma University Graduate School of Medicine.
    Kusakari, Shinya
    Gunma University.
    Hayashi, Yuriko
    Gunma University.
    Takao, Keizo
    Kyoto University Graduate School of Medicine, Fujita Health University.
    Maruyama, Toshi
    Gunma University.
    Ago, Yukio
    Osaka University.
    Koda, Ken
    Jin, Feng-Jie
    Gunma University.
    Okawa, Katsuya
    Kyowa Hakko Kirin Company Ltd., Takasaki.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Okazawa, Hideki
    Gunma University.
    Murata, Yoji
    Gunma University.
    Furuya, Nobuhiko
    Gunma University Graduate School of Medicine.
    Matsuda, Toshio
    Miyakawa, Tsuyoshi
    Kyoto University Graduate School of Medicine, Fujita Health University.
    Matozaki, Takashi
    Gunma University, Kobe University Graduate School of Medicine.
    Stress-evoked tyrosine phosphorylation of signal regulatory protein α regulates behavioral immobility in the forced swim test2010In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 30, no 31, p. 10472-10483Article in journal (Refereed)
    Abstract [en]

    Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.

  • 38.
    Okazawa, Hideki
    et al.
    Gunma University.
    Motegi, Sei-ichiro
    Gunma University.
    Ohyama, Naoko
    Gunma University.
    Ohnishi, Hiroshi
    Gunma University.
    Tomizawa, Takeshi
    Gunma University.
    Kaneko, Yoriaki
    Gunma University.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Ishikawa, Osamu
    Gunma University.
    Matozaki, Takashi
    Gunma University.
    Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system.2005In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 174, no 4, p. 2004-11Article in journal (Refereed)
    Abstract [en]

    Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that is expressed predominantly in macrophages. Its extracellular region interacts with the transmembrane ligand CD47 expressed on the surface of adjacent cells, and its cytoplasmic region binds the protein tyrosine phosphatases SHP-1 and SHP-2. Phagocytosis of IgG- or complement-opsonized RBCs by peritoneal macrophages derived from mice that express a mutant SHPS-1 protein that lacks most of the cytoplasmic region was markedly enhanced compared with that apparent with wild-type macrophages. This effect was not observed either with CD47-deficient RBCs as the phagocytic target or in the presence of blocking Abs to SHPS-1. Depletion of SHPS-1 from wild-type macrophages by RNA interference also promoted FcgammaR-mediated phagocytosis of wild-type RBCs. Ligation of SHPS-1 on macrophages by CD47 on RBCs promoted tyrosine phosphorylation of SHPS-1 and its association with SHP-1, whereas tyrosine phosphorylation of SHPS-1 was markedly reduced in response to cross-linking of FcgammaRs. Treatment with inhibitors of PI3K or of Syk, but not with those of MEK or Src family kinases, abolished the enhancement of FcgammaR-mediated phagocytosis apparent in macrophages from SHPS-1 mutant mice. In contrast, FcgammaR-mediated tyrosine phosphorylation of Syk, Cbl, or the gamma subunit of FcR was similar in macrophages from wild-type and SHPS-1 mutant mice. These results suggest that ligation of SHPS-1 on macrophages by CD47 promotes the tyrosine phosphorylation of SHPS-1 and thereby prevents the FcgammaR-mediated disruption of the SHPS-1-SHP-1 complex, resulting in inhibition of phagocytosis. The inhibition of phagocytosis by the SHPS-1-SHP-1 complex may be mediated at the level of Syk or PI3K signaling.

  • 39.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    CD47: a cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease.2013In: ISRN Hematology, ISSN 2090-441X, E-ISSN 2090-4428, Vol. 2013, p. 614619-Article in journal (Refereed)
    Abstract [en]

    Interactions between cells and their surroundings are important for proper function and homeostasis in a multicellular organism. These interactions can either be established between the cells and molecules in their extracellular milieu, but also involve interactions between cells. In all these situations, proteins in the plasma membranes are critically involved to relay information obtained from the exterior of the cell. The cell surface glycoprotein CD47 (integrin-associated protein (IAP)) was first identified as an important regulator of integrin function, but later also was shown to function in ways that do not necessarily involve integrins. Ligation of CD47 can induce intracellular signaling resulting in cell activation or cell death depending on the exact context. By binding to another cell surface glycoprotein, signal regulatory protein alpha (SIRPα), CD47 can regulate the function of cells in the monocyte/macrophage lineage. In this spotlight paper, several functions of CD47 will be reviewed, although some functions may be more briefly mentioned. Focus will be on the ways CD47 regulates hematopoietic cells and functions such as CD47 signaling, induction of apoptosis, and regulation of phagocytosis or cell-cell fusion.

  • 40.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Role of CD47 and Signal Regulatory Protein Alpha (SIRP alpha) in Regulating the Clearance of Viable or Aged Blood Cells2012In: Transfusion Medicine and Hemotherapy, ISSN 1660-3796, E-ISSN 1660-3818, Vol. 39, no 5, p. 315-320Article, review/survey (Refereed)
    Abstract [en]

    The ubiquitously expressed cell surface glycoprotein CD47 is expressed by virtually all cells in the host, where it can function to regulate integrin-mediated responses, or constitute an important part of the erythrocyte band 3/Rh multi-protein complex. In addition, CD47 can protect viable cells from being phagocytosed by macrophages or dendritic cells. The latter mechanism is dependent on the interaction between target cell CD47 and SIRP on the phagocyte. In this context, SIRP functions to inhibit prophagocytic signaling from Fc gamma receptors, complement receptors, and LDL receptor-related protein-1 (LRP-1), but not scavenger receptors. The expression level and/or distribution of CD47 may be altered on the surface of apoptotic/senescent cells, rendering the phagocytosis inhibitory function of the CD47/SIRP interaction reduced or eliminated. Instead, the interaction between these 2 proteins may serve to enhance the binding of apoptotic/senescent target cells to the phagocyte to promote phagocytosis.

  • 41.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Role of CD47 in erythroid cells and in autoimmunity.2004In: Leukemia & Lymphoma, ISSN 1042-8194, Vol. 45, no 7, p. 1319-27Article in journal (Other academic)
    Abstract [en]

    The cell surface glycoprotein CD47 (Integrin-associated protein/IAP) was originally identified as a regulator of integrin-dependent responses to extracellular matrix proteins. However, CD47 is ubiquitously expressed, also by cells that do not express integrins. Thus, during the last few years, it has been shown that CD47 has several important functions besides assisting integrin activation. This review will focus on the role of CD47 in erythrocytes. In these cells, CD47 was found to be an important link in the interaction between the band 3 complex and the Rh complex in the maintenance of erythrocyte membrane integrity. CD47 can also function as a marker of self on erythrocytes, and likely also on other cells, by binding to the inhibitory receptor SIRPalpha. In this way, SIRPalpha-expressing cells, like macrophages and dendritic cells, are less likely to phagocytose an autoimmune sensitized cell with CD47 on its surface than a CD47-deficient cell where this inhibitory mechanism will not be engaged. The interaction between CD47 and SIRPalpha seems to be important to limit destruction of host cells in autoimmune diseases like autoimmune hemolytic anemia (AIHA), where macrophages destroy antibody or complement opsonized cells.

  • 42.
    Oldenborg, Per-Arne
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Gresham, Hattie D
    Chen, Yongmei
    Izui, Shozo
    Lindberg, Frederik P
    Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic (NOD) mice.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 99, no 10, p. 3500-4Article in journal (Refereed)
    Abstract [en]

    The glycoprotein CD47 (integrin-associated protein, IAP) is present on the surface of virtually all cells, including red blood cells (RBCs). CD47 acts like a marker of self by ligating the macrophage inhibitory receptor signal regulatory protein alpha (SIRPalpha). In this manner mild reactivity of wild-type RBCs with macrophage phagocytic receptors is tolerated, whereas otherwise identical CD47-deficient RBCs are rapidly eliminated. We show here that virtually all CD47-deficient nonobese diabetic (NOD) mice spontaneously develop severe lethal autoimmune hemolytic anemia (AIHA) at 180 to 280 days of age, whereas none of the control CD47(+) NOD mice develop lethal AIHA at least during the first year of life. This phenotype is at least partially due to a markedly increased rate of elimination of opsonized CD47(-/-) compared to CD47(+) RBCs. Similarly, CD47(-/-)C57BL/6 mice were much more sensitive than their wild-type counterparts to experimental passive AIHA induced by anti-RBC monoclonal antibodies. Thus, CD47-SIRPalpha signaling can have a profound influence on the severity of AIHA, making manipulation of this signaling pathway a theoretically appealing avenue in the treatment of the disease.

  • 43.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology. Histologi med cellbiologi.
    Bruhns, Pierre
    Frazier, William A
    Ravetch, Jeffrey V
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology. Histologi med cellbiologi.
    Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia.2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 9, p. 3577-3582Article in journal (Refereed)
    Abstract [en]

    Interaction between target cell CD47 and the inhibitory macrophage receptor signal regulatory protein alpha (SIRPalpha) counteracts macrophage phagocytosis of CD47-expressing host cells. As platelets also express CD47, we asked whether inhibitory CD47/SIRPalpha signaling regulates normal platelet turnover and clearance of platelets in immune thrombocytopenic purpura (ITP). CD47(-/-) mice had a mild spontaneous thrombocytopenia, which was not due to a decreased platelet half-life as a result of increased expression of P-selectin, CD61, or phosphatidylserine. In contrast, CD47(-/-) platelets were rapidly cleared when transfused into CD47(+/+) recipients, whereas CD47(+/-) platelets had a nearly normal half-life in CD47(+/+) mice under nonautoimmune conditions. CD47(-/-) mice were more sensitive to ITP, as compared with CD47(+/+) mice. In vitro, macrophage phagocytosis of immunoglobulin G (IgG)-opsonized CD47(-/-) platelets was significantly higher than that for equally opsonized CD47(+/+) platelets. However, when SIRPalpha was blocked, phagocytosis of CD47(+/+) platelets increased to the level of CD47(-/-) platelets. Phagocytosis of opsonized CD47(+/-) platelets was higher than that for CD47(+/+) platelets, but lower than that for CD47(-/-) platelets, suggesting a gene-dose effect of CD47 in this system. In conclusion, we suggest that inhibitory CD47/SIRPalpha signaling is involved in regulating platelet phagocytosis in ITP, and that targeting SIRPalpha may be a new means of reducing platelet clearance in ITP.

  • 44.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Hagnerud, Sven
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Hedelius, David U R
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Hematologic Diseases: Autoimmune Hemolytic Anemia and Immune Thrombocytopenic Purpura2006In: Immunogenetics of Autoimmune Disease, 2006Chapter in book (Other academic)
    Abstract [en]

    Summary

    Autoinimune destruction of circularing blood cells in autoummunc hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) is often seen in autoirnnsune diseases and lymhoid malignancies. Erythrocytes or platelets that arc recognized by autoantibodues are rapidly phagocytosed by rnacrophages. Although much is known about the mechanisms behind macrophage-mediated destruction of sensitized blood cells, 1ess is known about the genetics behind AIHA and ITP. We here review what is known about the ethiology of Al 1-IA and lip, with particular emphasis on the role olgenetic factors behind auroanribody production. 1 cell activation and apoptosis, and Fcy receptor polymorphisms. The importance of inhibitory regulation oi rnacrophagcs through CD47IS[RPa interaction, and its significance for autoirnmune hemarological disease is also discussed.

  • 45.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Histologi med cellbiologi.
    Nilsson, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Histologi med cellbiologi.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Histologi med cellbiologi.
    Dose-dependent inhibitory effect of CD47 in macrophage uptake of IgG-opsonized murine erythrocytes.2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 1, p. 193-197Article in journal (Refereed)
    Abstract [en]

    The cell surface glycoprotein CD47 on target cells can bind to the inhibitory receptor SIRPalpha on macrophages to inhibit phagocytosis of antibody sensitized blood cells. The aim of this study was to determine if CD47 dose-dependently can regulate macrophage uptake of IgG-opsonized RBCs. CD47(+/-) RBCs express about 50% of the CD47 level found on CD47(+/+) RBCs. When injected into CD47(+/+) mice, CD47(+/-) RBCs showed a significantly faster antibody-mediated clearance as compared with CD47(+/+) RBCs injected into the same recipient. In vitro phagocytosis experiments confirmed that CD47(+/-) RBCs were taken up significantly more than CD47(+/+) RBCs, but significantly less than CD47(-/-) RBCs. A reduction in RBC CD47 expression just below 50% of that in normal RBCs can significantly accelerate RBC clearance by macrophages in the presence of RBC autoantibodies. This may have relevance for transfusion of stored RBCs, where loss of CD47 is seen over time, and in clearance of these cells by antibody-dependent phagocytosis.

  • 46.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Nilsson, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Target cell CD47 regulates macrophage activation and erythrophagocytosis.2006In: Transfusion Clinique et Biologique, ISSN 1246-7820, Vol. 13, no 1-2, p. 39-43Article in journal (Refereed)
    Abstract [en]

    The ubiquitously expressed cell surface glycoprotein CD47 (integrin-associated protein, IAP) was originally identified as a regulator of integrin-dependent leukocyte responses to extracellular matrix proteins. However, it has been shown that CD47 has several important functions in addition to regulating integrin activation. Extensive studies in murine systems have shown that CD47 on erythrocytes and other cells can function as a regulator of target cell phagocytosis, by binding to the inhibitory receptor SIRPalpha on macrophages. In this way, macrophages are less likely to phagocytose an autoimmune sensitized cell with CD47 on its surface than a CD47-deficient cell where this inhibitory mechanism will not be engaged. The CD47-SIRPalpha interaction seems to be important in limiting destruction of host cells in experimental models of autoimmune diseases like autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia, where macrophages destroy antibody or complement opsonized cells.

  • 47.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcgamma receptor-mediated but not scavenger receptor-mediated recognition by macrophages.2008In: Blood, ISSN 1528-0020, Vol. 112, no 10, p. 4259-67Article in journal (Refereed)
    Abstract [en]

    CD47 functions as a marker of self on red blood cells (RBCs) by binding to signal regulatory protein alpha on macrophages, preventing phagocytosis of autologous RBCs by splenic red pulp macrophages, and Fcgamma receptor (FcgammaR)- or complement receptor-mediated phagocytosis by macrophages in general. RBC senescence involves a series of biochemical changes to plasma membrane proteins or lipids, which may regulate phagocytosis by macrophages. Here, we investigated whether CD47 on experimentally senescent murine RBCs affects their phagocytosis by macrophages in vitro. Clustering of CD47 with antibodies was more pronounced in the plasma membrane of untreated RBCs, compared with that in in vitro oxidized RBCs (Ox-RBCs). Phagocytosis of Ox-RBCs was mediated by scavenger receptors (SRs) distinct from SR-A or CD36 and required serum factors. We found that wild-type (WT) and CD47(-/-) Ox-RBCs were phagocytosed equally well by macrophages in the presence of serum, suggesting that phagocytosis via SRs is not inhibited by CD47. Despite this, FcgammaR-mediated phagocytosis of IgG-opsonized Ox-RBCs was strongly inhibited by CD47. These data suggest that based on the specific prophagocytic receptors mediating uptake of senescent RBCs, the phagocytosis-inhibitory role of CD47 may be more or less involved.

  • 48.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    CD47 on experimentally senescent RBCs inhibits phagocytosis following Fcγ receptor-mediated but not scavenger receptor-mediated recognition by macrophagesManuscript (Other academic)
  • 49.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Spatial regulation of Fcγ receptor-mediated phagocytosis by the inhibitory CD47/SIRPα interactionManuscript (Other academic)
  • 50. Qadri, Syed M.
    et al.
    Bissinger, Rosi
    Solh, Ziad
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes2017In: Blood reviews, ISSN 0268-960X, E-ISSN 1532-1681, Vol. 31, no 6, p. 349-361Article, review/survey (Refereed)
    Abstract [en]

    During the course of their natural ageing and upon injury, anucleate erythrocytes can undergo an unconventional apoptosis-like cell death, termed eryptosis. Eryptotic erythrocytes display a plethora of morphological alterations including volume reduction, membrane blebbing and breakdown of the membrane phospholipid asymmetry resulting in phosphatidylserine externalization which, in turn, mediates their phagocytic recognition and clearance from the circulation. Overall, the eryptosis machinery is tightly orchestrated by a wide array of endogenous mediators, ion channels, membrane receptors, and a host of intracellular signaling proteins. Enhanced eryptosis shortens the lifespan of circulating erythrocytes and confers a procoagulant phenotype; this phenomenon has been tangibly implicated in the pathogenesis of anemia, deranged microcirculation, and increased prothrombotic risk associated with a multitude of clinical conditions. Herein, we reviewed the molecular mechanisms dictating eryptosis and erythrophagocytosis and critically analyzed the current evidence leading to the pathophysiological ramifications of eryptotic cell death in the context of human disease.

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