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Oldenborg, Per-Arne
Publications (10 of 65) Show all publications
Sato-Hashimoto, M., Nozu, T., Toriba, R., Horikoshi, A., Akaike, M., Kawamoto, K., . . . Ohnishi, H. (2019). Microglial SIRP alpha regulates the emergence of CD11c(+) microglia and demyelination damage in white matter. eLIFE, 8, Article ID e42025.
Open this publication in new window or tab >>Microglial SIRP alpha regulates the emergence of CD11c(+) microglia and demyelination damage in white matter
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e42025Article in journal (Refereed) Published
Abstract [en]

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c(+) microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein alpha (SIRP alpha), a membrane protein, induced the emergence of CD11c(+) microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRP alpha, and microglia-specific SIRP alpha-knockout mice exhibited the same phenotype, suggesting that an interaction between microglial SIRP alpha and CD47 on neighbouring cells suppressed the emergence of CD11c(+) microglia. A lack of SIRP alpha did not cause detectable damage to the white matter, but resulted in the increased expression of genes whose expression is characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRP alpha. Thus, microglial SIRP alpha suppresses the induction of CD11c(+) microglia that have the potential to accelerate the repair of damaged white matter.

Place, publisher, year, edition, pages
eLIFE Sciences Publications, 2019
Identifiers
urn:nbn:se:umu:diva-158095 (URN)10.7554/eLife.42025.001 (DOI)000462530500001 ()30910011 (PubMedID)
Available from: 2019-04-12 Created: 2019-04-12 Last updated: 2019-04-12Bibliographically approved
Murata, Y., Tanaka, D., Hazama, D., Yanagita, T., Saito, Y., Kotani, T., . . . Matozaki, T. (2018). Anti-human SIRP antibody is a new tool for cancer immunotherapy. Cancer Science, 109(5), 1300-1308
Open this publication in new window or tab >>Anti-human SIRP antibody is a new tool for cancer immunotherapy
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2018 (English)In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 109, no 5, p. 1300-1308Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
antibody, CD47, macrophage, phagocytosis, signal regulatory protein
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-150702 (URN)10.1111/cas.13548 (DOI)000434071400003 ()29473266 (PubMedID)
Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Yanagita, T., Murata, Y., Tanaka, D., Motegi, S.-i., Arai, E., Daniwijaya, E. W., . . . Matozaki, T. (2017). Anti-SIRP alpha antibodies as a potential new tool for cancer immunotherapy. JCI Insight, 2(1), Article ID e89140.
Open this publication in new window or tab >>Anti-SIRP alpha antibodies as a potential new tool for cancer immunotherapy
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2017 (English)In: JCI Insight, ISSN 2379-3708, Vol. 2, no 1, article id e89140Article in journal (Refereed) Published
Abstract [en]

Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRP alpha is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRP alpha is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRP alpha Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRP alpha signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8(+) T cells. In addition, the anti-SIRP alpha Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRP alpha-nonexpressing tumor cells. Anti-SIRP alpha Abs thus warrant further study as a potential new therapy for a broad range of cancers.

Place, publisher, year, edition, pages
American Society for Clinical Investigation, 2017
National Category
Cancer and Oncology Basic Medicine
Identifiers
urn:nbn:se:umu:diva-132153 (URN)10.1172/jci.insight.89140 (DOI)000393591600003 ()28097229 (PubMedID)
Note

Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-06-09Bibliographically approved
diva2:1165990
Open this publication in new window or tab >>Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes
2017 (English)In: Blood reviews, ISSN 0268-960X, E-ISSN 1532-1681, Vol. 31, no 6, p. 349-361Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
CHURCHILL LIVINGSTONE, 2017
Keywords
Erythrocytes, Apoptosis, Eryptosis, Senescence, Erythirophagocytosis, Hemolysis, Anemia, Thrombosis, Deranged microcirculation
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-142939 (URN)10.1016/j.blre.2017.06.001 (DOI)000416204900001 ()28669393 (PubMedID)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
Meinderts, S. M., Oldenborg, P.-A., Beuger, B. M., Klei, T. R. L., Johansson, J., Kuijpers, T. W., . . . Van Bruggen, R. (2017). Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells. Blood Advances, 1(14), 875-886
Open this publication in new window or tab >>Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells
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2017 (English)In: Blood Advances, ISSN 2473-9529, Vol. 1, no 14, p. 875-886Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society of Hematology, 2017
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-137381 (URN)10.1182/bloodadvances.2017004671 (DOI)000403209800003 ()
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2018-06-09Bibliographically approved
Meinderts, S. M., Oldenborg, P.-A., Beuger, B., Kuijpers, T. W., van den Berg, T. K. & van Bruggen, R. (2016). Antibody-mediated phagocytosis of red blood cells by neutrophils in the human spleen. European Journal of Clinical Investigation, 46, 77-77
Open this publication in new window or tab >>Antibody-mediated phagocytosis of red blood cells by neutrophils in the human spleen
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2016 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 46, p. 77-77Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-121586 (URN)000375378000183 ()
Available from: 2016-06-23 Created: 2016-06-03 Last updated: 2018-06-07Bibliographically approved
Holm, C. K., Engman, S., Sulniute, R., Matozaki, T., Oldenborg, P.-A. & Lundberg, P. (2016). Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation. Biochemical and Biophysical Research Communications - BBRC, 478(1), 268-273
Open this publication in new window or tab >>Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation
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2016 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 478, no 1, p. 268-273Article in journal (Refereed) Published
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. 

National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-126495 (URN)10.1016/j.bbrc.2016.07.048 (DOI)000381332800041 ()27422603 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-10 Last updated: 2018-06-09Bibliographically approved
Larsson, A., Hult, A., Nilsson, A., Olsson, M. & Oldenborg, P.-A. (2016). Red blood cells with elevated cytoplasmic Ca2+ are primarily taken up by splenic marginal zone macrophages and CD207+dendritic cells. Transfusion, 56(7), 1834-1844
Open this publication in new window or tab >>Red blood cells with elevated cytoplasmic Ca2+ are primarily taken up by splenic marginal zone macrophages and CD207+dendritic cells
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2016 (English)In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 56, no 7, p. 1834-1844Article in journal (Refereed) Published
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.

National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-125594 (URN)10.1111/trf.13612 (DOI)000380362100025 ()27095001 (PubMedID)
Available from: 2016-09-23 Created: 2016-09-13 Last updated: 2018-06-07Bibliographically approved
Kolan, S., Boman, A., Matozaki, T., Lejon, K. & Oldenborg, P.-A. (2015). Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells. Biochemical and Biophysical Research Communications - BBRC, 460(3), 645-650
Open this publication in new window or tab >>Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells
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2015 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 460, no 3, p. 645-650Article in journal (Refereed) Published
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.

Keywords
Marginal zone B cells, Signal regulatory protein alpha, Marginal zone macrophages
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107627 (URN)10.1016/j.bbrc.2015.03.084 (DOI)000359885300026 ()
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2018-06-07Bibliographically approved
Kolan, S., Lejon, K., Koskinen Holm, C., Sulniute, R., Lundberg, P., Matozaki, T. & Oldenborg, P.-A. (2015). Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen. PLoS One, 10(7), Article ID e0134113.
Open this publication in new window or tab >>Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen
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2015 (English)In: PLoS One, Vol. 10, no 7, article id e0134113Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
plos one, 2015
Keywords
B cells, Bone marrow, Follicular B cells
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107619 (URN)10.1371/journal.pone.0134113 (DOI)000358836800105 ()
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2018-06-07Bibliographically approved
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