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  • 1.
    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.

  • 2.
    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.

  • 3.
    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.

  • 4.
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Studies of SIRPα-mediated regulation of neutrophil functions2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neutrophil granulocytes constitute the front line of defense in the innate immune response to invading microorganisms, but can also contribute to development of inflammatory disease and tissue destruction following e.g. myocardial infarction or stroke. During inflammatory activation, neutrophils leave the blood, interact with extracellular matrix proteins, and migrate into tissues in response to chemotactic factors to phagocytose and kill infectious agents by using toxic granule contents and reactive oxygen metabolites. The functional neutrophil response relies on exocytosis of cytoplasmic granules, each containing membrane proteins, which are thereby mobilized to the plasma membrane. Specific programmed cell death (apoptotic) pathways regulate neutrophil homeostasis, where an inflammatory milieu can prolong the life span of neutrophils to several days, whereas non-activated neutrophils are committed to constitutive/spontaneous apoptosis within hours.

    Signal regulatory protein alpha (SIRPα) is a surface glycoprotein with two intracellular immunoreceptor-tyrosine-based inhibitory motifs (ITIMs), which is highly expressed in neutrophils and other myeloid cells. In other cell types, SIRPα has been shown to regulate cellular functions such as cell migration and phagocytosis. The aim of the present thesis was to investigate neutrophil SIRPα expression in response to inflammatory activation or apoptosis, and how this receptor can regulate neutrophil adhesion and cell migration.

    Neutrophils contain several subcellular granule compartments, including primary (azurophilic), secondary (specific), tertiary (gelatinase) granules, and a fourth compartment called secretory vesicles. In resting neutrophils, SIRPα was found to be present in the plasma membrane and in all types of granules except for the azurophilic granules. Stimulation with the bacterial peptide fMLF in vitro, or inflammatory activation in vivo, was found to rapidly mobilize SIRPα to the neutrophil cell surface. In mice expressing a mutated form of SIRPα, where the cytoplasmic signaling domain was deleted, we found an enhanced accumulation of neutrophils in the peritoneal cavity in a peritonitis model. These findings therefore suggest that an increased amount of SIRPα on the surface of activated neutrophils could serve to negatively fine-tune neutrophil accumulation in inflammation.

    Neutrophil priming means that the cell becomes partially activated, in a way that facilitates subsequent full activation. One part of the priming process is a moderate exocytosis of granules, mostly the secretory vesicles, which increases the density of certain receptors on the cell surface. It also involves the activation of adhesion receptors called integrins. We found that TNFα-induced priming involved an increased accumulation of SIRPα on the cell surface. When comparing wild-type and SIRPα-mutant neutrophils, we found a strongly reduced TNFα-stimulated and β2 integrin-dependent adhesion of mutant neutrophils to type I collagen or fibrinogen. This adhesion defect resulted in a reduced adhesion-dependent activation of the respiratory burst and an increased chemotactic response of SIRPα-mutant neutrophils in vitro.

    During neutrophil apoptosis, several receptors are known to be shed from the cell surface (e.g. CD16 and CD43). We found that also SIRPα is shed from the surface during spontaneous as well as Fas-induced apoptosis. The shedding mechanism was found to involve matrix metalloproteinase (MMP) activity, mostly that of MMP-3 and MMP-8.

    In conclusion, neutrophil cell surface SIRPα expression is regulated during neutrophil activation and seems to play an important role in stimulating β2-integrin-dependent adhesion. This way, SIRPα can negatively fine-tune neutrophil migration and accumulation in inflammation. During apoptosis, SIRPα is shed from the cell surface, which may be one mechanism contributing to the well-known down-regulation in the adhesiveness of apoptotic neutrophils.

  • 5.
    Stenberg, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Karlsson, Anna
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Feuk-Lagerstedt, Elisabeth
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Christenson, Karin
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Bylund, Johan
    Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Oldenborg, Anna
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Mo. , USA.
    Vesterlund, Liselotte
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology. Department of Biosciences and Nutrition at Novum, Karolinska Institute, Stockholm , Sweden.
    Matozaki, Takashi
    Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe , Japan.
    Sehlin, Janove
    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.
    Signal regulatory protein alpha is present in several neutrophil granule populations and is rapidly mobilized to the cell surface to negatively fine-tune neutrophil accumulation in inflammation2014In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, no 4, p. 553-560Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein alpha (SIRPα) is a cell surface glycoprotein with inhibitory functions, which may regulate neutrophil transmigration. SIRPα is mobilized to the neutrophil surface from specific granules, gelatinase granules, and secretory vesicles following inflammatory activation in vitro and in vivo. The lack of SIRPα signaling and the ability to upregulate SIRPα to the cell surface promote neutrophil accumulation during inflammation in vivo.

  • 6.
    Stenberg, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Sehlin, Janove
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Signal regulatory protein alpha (SIRPα) negatively regulates neutrophil migration by stimulating β2 integrin-mediated adhesionManuscript (preprint) (Other academic)
  • 7.
    Stenberg, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Sehlin, Janove
    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.
    Neutrophil apoptosis is associated with loss of signal regulatory protein alpha (SIRP alpha) from the cell surface2013In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 93, no 3, p. 403-412Article in journal (Refereed)
    Abstract [en]

    Cells of the innate immune system, including monocytes, macrophages, and neutrophils, play a major role in the development of inflammatory diseases. During inflammation, large numbers of neutrophils are recruited from the blood and subsequently undergo apoptosis, which involves changes in the cell surface expression of a number of receptors. Neutrophils express the Ig superfamily member, SIRP alpha, which is a receptor involved in regulating cell adhesion and migration. As apoptotic neutrophils down-regulate their capacity for adhesion and migration, we here investigated whether neutrophil expression of SIRP alpha was affected during apoptosis. We found that apoptotic neutrophils lost SIRP alpha from their cell surface with kinetics similar to the loss of CD16. The majority of neutrophils with reduced SIRP alpha also expressed PS on their surface, and the loss of the receptor was reduced proportional to the reduction of apoptosis by caspase inhibitors during Fas-induced apoptosis but less so during spontaneous apoptosis. Neutrophil loss of SIRP alpha or CD16 was inhibited by the protease inhibitor TAPI-2, as well as specific inhibitors of MMP3 or -8, suggesting that proteolytic mechanisms were involved. Finally, SIRP alpha was also found on smaller membrane vesicles released from the cells during apoptosis. Our data suggest that neutrophils reduce their SIRP alpha expression during apoptosis, which may be part of the functional down-regulation seen in apoptotic neutrophils. J. Leukoc. Biol. 93: 403-412; 2013.

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