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Kevin Croce - One of the best experts on this subject based on the ideXlab platform.
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cd43 functions as an e selectin ligand for th17 cells in vitro and is required for rolling on the vascular endothelium and th17 cell recruitment during inflammation in vivo
Journal of Immunology, 2016Co-Authors: Kevin Croce, Francisco Velazquez, Anna Grodeckipena, Andrew Knapp, Ane M Salvador, Tania Nevers, Pilar AlcaideAbstract:Endothelial E- and P-selectins mediate lymphocyte trafficking in inflammatory processes by interacting with lymphocyte selectin ligands. These are differentially expressed among different T cell subsets and function alone or in cooperation to mediate T cell adhesion. In this study, we characterize the expression and functionality of E-selectin ligands in Th type 17 lymphocytes (Th17 cells) and report that CD43 functions as a Th17 cell E-selectin ligand in vitro that mediates Th17 cell rolling on the vascular endothelium and recruitment in vivo. We demonstrate Th17 cells express CD44, P-selectin glycoprotein ligand (PSGL)-1, and CD43. Few PSGL-1(-/-)CD43(-/-) Th17 cells accumulated on E-selectin under shear flow conditions compared with wild-type cells. CD43(-/-) Th17 cell accumulation on E-selectin was impaired as compared with wild-type and PSGL-1(-/-), and similar to that observed for PSGL-1(-/-)CD43(-/-) Th17 cells, indicating that CD43 alone is a dominant ligand for E-selectin. Notably, this finding is Th17 cell subset specific because CD43 requires cooperation with PSGL-1 in Th1 cells for binding to E-selectin. In vivo, Th17 cell recruitment into the air pouch was reduced in CD43(-/-) mice in response to CCL20 or TNF-α, and intravital microscopy studies demonstrated that CD43(-/-) Th17 cells had impaired rolling on TNF-α-treated microvessels. Furthermore, CD43(-/-) mice were protected from experimental autoimmune encephalomyelitis and had impaired recruitment of Th17 cells in the spinal cord. Our findings demonstrate that CD43 is a major E-selectin ligand in Th17 cells that functions independent of PSGL-1, and they suggest that CD43 may hold promise as a therapeutic target to modulate Th17 cell recruitment.
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endothelial CD47 promotes vascular endothelial cadherin tyrosine phosphorylation and participates in t cell recruitment at sites of inflammation in vivo
Journal of Immunology, 2012Co-Authors: Veronica Azcutia, Michael Stefanidakis, Naotake Tsuboi, Kevin Croce, Tanya N MayadasAbstract:At sites of inflammation, endothelial adhesion molecules bind leukocytes and transmit signals required for transendothelial migration (TEM). We previously reported that adhesive interactions between endothelial cell CD47 and leukocyte signal regulatory protein γ (SIRPγ) regulate human T cell TEM. The role of endothelial CD47 in T cell TEM in vivo, however, has not been explored. In this study, CD47−/− mice showed reduced recruitment of blood T cells as well as neutrophils and monocytes in a dermal air pouch model of TNF-α–induced inflammation. Reconstitution of CD47−/− mice with wild-type bone marrow cells did not restore leukocyte recruitment to the air pouch, indicating a role for endothelial CD47. The defect in leukocyte TEM in the CD47−/− endothelium was corroborated by intravital microscopy of inflamed cremaster muscle microcirculation in bone marrow chimera mice. In an in vitro human system, CD47 on both HUVEC and T cells was required for TEM. Although previous studies showed CD47-dependent signaling required Gαi-coupled pathways, this was not the case for endothelial CD47 because pertussis toxin, which inactivates Gαi, had no inhibitory effect, whereas Gαi was required by the T cell for TEM. We next investigated the endothelial CD47-dependent signaling events that accompany leukocyte TEM. Ab-induced cross-linking of CD47 revealed robust actin cytoskeleton reorganization and Src- and Pyk-2–kinase dependent tyrosine phosphorylation of the vascular endothelial-cadherin cytoplasmic tail. This signaling was pertussis toxin insensitive, suggesting that endothelial CD47 signaling is independent of Gαi. These findings suggest that engagement of endothelial CD47 by its ligands triggers outside-in signals in endothelium that facilitate leukocyte TEM.
Yong-guang Yang - One of the best experts on this subject based on the ideXlab platform.
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Human CD47 Expression Permits Survival of Porcine Cells in Immunodeficient Mice that Express SIRPα Capable of Binding to Human CD47
Cell transplantation, 2011Co-Authors: Chunfeng Wang, Hui Wang, Nico Van Rooijen, Kentaro Ide, Yuantao Wang, Hideki Ohdan, Yong-guang YangAbstract:Signal regulatory protein α (SIRPα) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47 prevents autologous phagocytosis. We have previously shown that pig CD47 does not interact with human SIRPα, and that human CD47 expression inhibits phagocytosis of porcine cells by human macrophages in vitro. In this study, we have investigated the potential of human CD47 expression to promote porcine cell survival in vivo. Human CD47-expressing and control porcine B-lymphoma cells were transplanted into T and B cell-deficient non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice that express SIRPα capable of interacting with human CD47. Only the human CD47-expressing porcine lymphoma cells survived and were able to form tumors in NOD/SCID mice; however, both the control and human CD47-expressing porcine cells survived in macrophage-depleted NOD/SCID mice. These results indicate that transgenic expression of human CD47 may provide an effective approach to inhibiting macrophage-mediated xenograft rejection in clinical xenotransplantation.
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Survival and function of CD47‐deficient thymic grafts in mice
Xenotransplantation, 2010Co-Authors: Yuantao Wang, Hui Wang, Shumei Wang, Yong-guang YangAbstract:Wang Y, Wang H, Wang S, Fu Y, Yang Y-G. Survival and function of CD47-deficient thymic grafts in mice. Xenotransplataion 2010; 17: 160–165. © 2010 John Wiley & Sons A/S. Abstract: Background: We have previously shown that the interspecies incompatibility of CD47 plays an important role in triggering rejection of xenogeneic hematopoietic cells by macrophages. However, it remains unknown whether CD47 incompatibility also contributes to the rejection of non-hematopoietic xenografts. Aims: Here, we investigated the role of CD47 in preventing macrophage-mediated rejection of thymic epithelial cells in a mouse model of thymic transplantation across the CD47 barrier. Methods: Wild-type (WT) and CD47 KO mice were thymectomized and treated with T cell-depleting mAbs, and implanted with fetal thymus from syngeneic WT or CD47 KO donors. Results: Transplantation of CD47 KO mouse thymus led to T cell recovery in thymectomized, T cell-depleted WT mice. Similar to the control WT mouse thymic grafts, CD47 KO mouse thymic grafts showed a normal distribution of thymocyte subsets, and almost all of the thymocytes were recipient origin. Furthermore, histological analysis confirmed long-term survival of CD47 KO mouse thymic epithelial cells in WT mouse recipients. Conclusions: These results demonstrate that, unlike hematopoietic cells, CD47 KO mouse thymus can survive and function in WT mice. Furthermore, our data implicate that the role of CD47 in xenograft rejection may differ for different types of xenografts, and that CD47 incompatibility is unlikely to impede thymic xenotransplantation, a potential approach to inducing xenotolerance, by triggering macrophage-mediated rejection.
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Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Hui Wang, Maria Lucia L. Madariaga, Shumei Wang, Nico Van Rooijen, Per-arne Oldenborg, Yong-guang YangAbstract:Macrophages recognize CD47 as a marker of "self" and phagocytose CD47(null) hematopoietic cells. Using CD47 chimera models, here, we show that the phagocytic activity of macrophages against CD47(null) hematopoietic cells is conferred by CD47 expression on nonhematopoietic cells, and this "education" process is hematopoietic cell-independent. Macrophages in the chimeras where nonhematopoietic cells express CD47 phagocytose CD47(null) cells, whereas those in the chimeras lacking CD47 on nonhematopoietic cells are tolerant to CD47(null) cells. However, macrophages in the latter chimeras retain phagocytic activity against CD47(null) RBCs, demonstrating a split macrophage tolerance to CD47(null) hematopoietic cells. The findings highlight the potential importance of nonhematopoietic cells in the regulation of macrophage function, and suggest a previously uncharacterized mechanism of macrophage tolerance.
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Attenuation of phagocytosis of xenogeneic cells by manipulating CD47.
Blood, 2006Co-Authors: Hui Wang, Maria Lucia L. Madariaga, Shumei Wang, Per-arne Oldenborg, Jon Verhalen, Shuanglin Xiang, Ping Lan, Megan Sykes, Yong-guang YangAbstract:Signal regulatory protein α (SIRPα) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, prevents autologous phagocytosis. We hypothesized that interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. Here, we show that pig CD47 does not interact with mouse SIPRα. Similar to CD47−/− mouse cells, porcine red blood cells (RBCs) failed to induce SIRPα tyrosine phosphorylation in mouse macrophages. Blocking SIRPα with antimouse SIRPα mAb (P84) significantly enhanced the phagocytosis of CD47+/+ mouse cells, but did not affect the engulfment of porcine or CD47−/− mouse cells by mouse macrophages. CD47-deficient mice, whose macrophages do not phagocytose CD47−/− mouse cells, showed markedly delayed clearance of porcine RBCs compared with wild-type mouse recipients. Furthermore, mouse CD47 expression on porcine cells markedly reduced their phagocytosis by mouse macrophages both in vitro and in vivo. These results indicate that interspecies incompatibility of CD47 contributes significantly to phagocytosis of xenogeneic cells by macrophages and suggest that genetic manipulation of donor CD47 to improve its interaction with the recipient SIRPα may provide a novel approach to prevent phagocyte-mediated xenograft rejection.
Lee Jia - One of the best experts on this subject based on the ideXlab platform.
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Checkpoint CD47 Function On Tumor Metastasis And Immune Therapy.
OncoTargets and therapy, 2019Co-Authors: Shu Lian, Xiaodong Xie, Lee JiaAbstract:The success of cancer immunotherapy on recognition checkpoints for killing cancer cells has raised a great interest of scientists in understanding new and old methods of immunotherapeutic. CD47 (cluster of differentiation 47) is a cell surface glycoprotein and widely expressed on cells, which belongs to the immunoglobulin (Ig) superfamily as a cell membrane receptor which serves in immune therapy. CD47 is an inhibitory receptor expressed on tumor cell surface and interacts with signal receptor protein-alpha (SIPR-α, also named CD172a or SHPS-1) which may escape from immune cells such as macrophage and T cells. Meanwhile, tumor cells express high CD47 protein which may secrete exosomes with high CD47 expression. The high CD47 expression-exosomes could serve the tumor metastasis process and provide transfer convenience for tumors on the microenvironment. CD47 on cancer cells can also affect the migration and invasion of cells. The high CD47 expression on tumor or CTC (circulating tumor cell) surface means the stronger migration and invasion and makes them escape from immune cells for phagocytosis such as T cells, NK (natural killer) cells and macrophage, which could be used for diagnosis and prognosis on cancer patients. Meanwhile, targeting CD47 combined with other biomarkers such as EpCAM (epithelial cell adhesion molecule), CD44, etc on cancer surface could be used to isolate CTCs from patients' blood. In terms of treatment, anti-CD47 antibody combined with another antibody such as anti-PD-L1 (programmed death-ligand 1) antibody or drugs such as rituximab, DOX or oxaliplatin also has better therapeutic effects and antitumor function to tumors. Using nanomaterials as an intermediary for CD47-related immune therapy could greatly increase the therapeutic effect and overcome multiple biological barriers for anti-CD47 antibody in vivo. In this review, we discuss the important role and the function of CD47 in tumor metastasis and also provide a reference for related research.
Veronica Azcutia - One of the best experts on this subject based on the ideXlab platform.
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Epithelial CD47 is critical for mucosal repair in the murine intestine in vivo.
Nature communications, 2019Co-Authors: Michelle Reed, Veronica Azcutia, Anny-claude Luissint, Shuling Fan, Monique N. O’leary, Miguel Quiros, Jennifer C. Brazil, Asma Nusrat, Charles A. ParkosAbstract:CD47 is a ubiquitously expressed transmembrane glycoprotein that regulates inflammatory responses and tissue repair. Here, we show that normal mice treated with anti-CD47 antibodies, and CD47-null mice have impaired intestinal mucosal wound healing. Furthermore, intestinal epithelial cell (IEC)-specific loss of CD47 does not induce spontaneous immune-mediated intestinal barrier disruption but results in defective mucosal repair after biopsy-induced colonic wounding or Dextran Sulfate Sodium (DSS)-induced mucosal damage. In vitro analyses using primary cultures of CD47-deficient murine colonic IEC or human colonoid-derived IEC treated with CD47-blocking antibodies demonstrate impaired epithelial cell migration in wound healing assays. Defective wound repair after CD47 loss is linked to decreased epithelial β1 integrin and focal adhesion signaling, as well as reduced thrombospondin-1 and TGF-β1. These results demonstrate a critical role for IEC-expressed CD47 in regulating mucosal repair and raise important considerations for possible alterations in wound healing secondary to therapeutic targeting of CD47.
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endothelial CD47 promotes vascular endothelial cadherin tyrosine phosphorylation and participates in t cell recruitment at sites of inflammation in vivo
Journal of Immunology, 2012Co-Authors: Veronica Azcutia, Michael Stefanidakis, Naotake Tsuboi, Kevin Croce, Tanya N MayadasAbstract:At sites of inflammation, endothelial adhesion molecules bind leukocytes and transmit signals required for transendothelial migration (TEM). We previously reported that adhesive interactions between endothelial cell CD47 and leukocyte signal regulatory protein γ (SIRPγ) regulate human T cell TEM. The role of endothelial CD47 in T cell TEM in vivo, however, has not been explored. In this study, CD47−/− mice showed reduced recruitment of blood T cells as well as neutrophils and monocytes in a dermal air pouch model of TNF-α–induced inflammation. Reconstitution of CD47−/− mice with wild-type bone marrow cells did not restore leukocyte recruitment to the air pouch, indicating a role for endothelial CD47. The defect in leukocyte TEM in the CD47−/− endothelium was corroborated by intravital microscopy of inflamed cremaster muscle microcirculation in bone marrow chimera mice. In an in vitro human system, CD47 on both HUVEC and T cells was required for TEM. Although previous studies showed CD47-dependent signaling required Gαi-coupled pathways, this was not the case for endothelial CD47 because pertussis toxin, which inactivates Gαi, had no inhibitory effect, whereas Gαi was required by the T cell for TEM. We next investigated the endothelial CD47-dependent signaling events that accompany leukocyte TEM. Ab-induced cross-linking of CD47 revealed robust actin cytoskeleton reorganization and Src- and Pyk-2–kinase dependent tyrosine phosphorylation of the vascular endothelial-cadherin cytoplasmic tail. This signaling was pertussis toxin insensitive, suggesting that endothelial CD47 signaling is independent of Gαi. These findings suggest that engagement of endothelial CD47 by its ligands triggers outside-in signals in endothelium that facilitate leukocyte TEM.
Takashi Matozaki - One of the best experts on this subject based on the ideXlab platform.
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Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system.
Journal of Cell Science, 2008Co-Authors: Shinya Kusakari, Hiroshi Ohnishi, Feng-jie Jin, Yuka Kaneko, Takaaki Murata, Yoji Murata, Hideki Okazawa, Takashi MatozakiAbstract:CD47 and SHPS-1 are transmembrane proteins that interact with each other through their extracellular regions and constitute a bidirectional cell-cell communication system (the CD47–SHPS-1 system). We have now shown that the trans-interaction of CD47 and SHPS-1 that occurred on contact of CD47-expressing CHO cells and SHPS-1-expressing CHO cells resulted in endocytosis of the ligand-receptor complex into either cell type. Such trans-endocytosis of CD47 by SHPS-1-expressing cells was found to be mediated by clathrin and dynamin. A juxtamembrane region of SHPS-1 was indispensable for efficient trans-endocytosis of CD47, which was also regulated by Rac and Cdc42, probably through reorganization of the actin cytoskeleton. Inhibition of trans-endocytosis of CD47 promoted the aggregation of CD47-expressing cells with the cells expressing SHPS-1. Moreover, CD47 expressed on the surface of cultured mouse hippocampal neurons was shown to undergo trans-endocytosis by neighboring astrocytes expressing endogenous SHPS-1. These results suggest that trans-endocytosis of CD47 is responsible for removal of the CD47–SHPS-1 complex from the cell surface and hence regulates the function of the CD47–SHPS-1 system, at least in neurons and glial cells.