The Experts below are selected from a list of 31683 Experts worldwide ranked by ideXlab platform

Mingwei Sheng - One of the best experts on this subject based on the ideXlab platform.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    Background and aims The cluster of differentiation 47 (CD47)-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. Approach and results In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity Protein 2), which in turn inhibited NEK7/NLRP3 activity. Conclusions The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    BACKGROUND & AIMS The CD47-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/SMO/Gli1 pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. APPROACH & RESULTS In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IRI. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD but enhanced NEK7 and NLRP3 activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2, which in turn inhibited NEK7/NLRP3 activity. CONCLUSIONS The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a novel coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide novel potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

Neil A Barclay - One of the best experts on this subject based on the ideXlab platform.

  • the interaction between signal regulatory Protein Alpha sirpα and cd47 structure function and therapeutic target
    Annual Review of Immunology, 2014
    Co-Authors: Neil A Barclay, Timo K Van Den Berg
    Abstract:

    CD47 is a broadly expressed membrane Protein that interacts with the myeloid inhibitory immunoreceptor SIRPα (also termed CD172a or SHPS-1). SIRPα is the prototypic member of the SIRP paired receptor family of closely related SIRP Proteins. Engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis, and CD47 therefore functions as a “don't-eat-me” signal. Here, we discuss recent structural analysis of CD47-SIRPα interactions and implications of this for the function and evolution of SIRPα and paired receptors in general. Furthermore, we review the proposed roles of CD47-SIRPα interactions in phagocytosis, (auto)immunity, and host defense, as well as its potential significance as a therapeutic target in cancer and inflammation and for improving graft survival in xenotransplantation.

  • the interaction between signal regulatory Protein Alpha sirpα and cd47 structure function and therapeutic target
    Annual Review of Immunology, 2014
    Co-Authors: Neil A Barclay, Timo K Van Den Berg
    Abstract:

    CD47 is a broadly expressed membrane Protein that interacts with the myeloid inhibitory immunoreceptor SIRPα (also termed CD172a or SHPS-1). SIRPα is the prototypic member of the SIRP paired receptor family of closely related SIRP Proteins. Engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis, and CD47 therefore functions as a "don't-eat-me" signal. Here, we discuss recent structural analysis of CD47-SIRPα interactions and implications of this for the function and evolution of SIRPα and paired receptors in general. Furthermore, we review the proposed roles of CD47-SIRPα interactions in phagocytosis, (auto)immunity, and host defense, as well as its potential significance as a therapeutic target in cancer and inflammation and for improving graft survival in xenotransplantation.

  • structure of signal regulatory Protein Alpha a link to antigen receptor evolution
    Journal of Biological Chemistry, 2009
    Co-Authors: Deborah Hatherley, Stephen C Graham, Karl Harlos, D I Stuart, Neil A Barclay
    Abstract:

    Signal-Regulatory Protein Alpha (SIRPAlpha) is a myeloid membrane receptor that interacts with the membrane Protein CD47, a marker of self. We have solved the structure of the complete extracellular portion of SIRPAlpha, comprising three immunoglobulin superfamily domains, by x-ray crystallography to 2.5 A resolution. These data, together with previous data on the N-terminal domain and its ligand CD47 (possessing a single immunoglobulin superfamily domain), show that the CD47-SIRPAlpha interaction will span a distance of around 14 nm between interacting cells, comparable with that of an immunological synapse. The N-terminal (V-set) domain mediates binding to CD47, and the two others are found to be constant (C1-set) domains. C1-set domains are restricted to Proteins involved in vertebrate antigen recognition: T cell antigen receptors, immunoglobulins, major histocompatibility complex antigens, tapasin, and beta2-microglobulin. The domains of SIRPAlpha (domains 2 and 3) are structurally more similar to C1-set domains than any cell surface Protein not involved in antigen recognition. This strengthens the suggestion from sequence analysis that SIRP is evolutionarily closely related to antigen recognition Proteins.

Jerzy W Kupiecweglinski - One of the best experts on this subject based on the ideXlab platform.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    Background and aims The cluster of differentiation 47 (CD47)-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. Approach and results In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity Protein 2), which in turn inhibited NEK7/NLRP3 activity. Conclusions The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    BACKGROUND & AIMS The CD47-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/SMO/Gli1 pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. APPROACH & RESULTS In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IRI. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD but enhanced NEK7 and NLRP3 activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2, which in turn inhibited NEK7/NLRP3 activity. CONCLUSIONS The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a novel coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide novel potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

Yuanbang Lin - One of the best experts on this subject based on the ideXlab platform.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    Background and aims The cluster of differentiation 47 (CD47)-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. Approach and results In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity Protein 2), which in turn inhibited NEK7/NLRP3 activity. Conclusions The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

  • cd47 mediated hedgehog smo gli1 signaling promotes mesenchymal stem cell immunomodulation in mouse liver inflammation
    Hepatology, 2021
    Co-Authors: Mingwei Sheng, Yuanbang Lin, Yizhu Tian, Yongqiang Zhan, Douglas G Farmer, Jerzy W Kupiecweglinski
    Abstract:

    BACKGROUND & AIMS The CD47-signal regulatory Protein Alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/SMO/Gli1 pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. APPROACH & RESULTS In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IRI. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD but enhanced NEK7 and NLRP3 activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2, which in turn inhibited NEK7/NLRP3 activity. CONCLUSIONS The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a novel coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide novel potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

Per-arne Oldenborg - One of the best experts on this subject based on the ideXlab platform.

  • 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 inflammation
    Journal of Innate Immunity, 2014
    Co-Authors: Asa Stenberg, Anna Karlsson, Elisabeth Feuklagerstedt, Karin Christenson, Johan Bylund, Anna Oldenborg, Liselotte Vesterlund, Takashi Matozaki, Janove Sehlin, Per-arne Oldenborg
    Abstract:

    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.

  • cd47 a cell surface glycoProtein which regulates multiple functions of hematopoietic cells in health and disease
    International Scholarly Research Notices, 2013
    Co-Authors: Per-arne Oldenborg
    Abstract:

    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.

  • 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
    Journal of Immunology, 2006
    Co-Authors: Sven Hagnerud, Asa Stenberg, Partha Pratim Manna, Marina Cella, William A Frazier, Marco Colonna, Per-arne Oldenborg
    Abstract:

    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.

  • Role of CD47 as a marker of self on red blood cells.
    Science (New York N.Y.), 2000
    Co-Authors: Per-arne Oldenborg, Alex Zheleznyak, Yi-fu Fang, Carl F. Lagenaur, Hattie D. Gresham, Frederik P. Lindberg
    Abstract:

    The immune system recognizes invaders as foreign because they express determinants that are absent on host cells or because they lack "markers of self" that are normally present. Here we show that CD47 (integrin-associated Protein) functions as a marker of self on murine red blood cells. Red blood cells that lacked CD47 were rapidly cleared from the bloodstream by splenic red pulp macrophages. CD47 on normal red blood cells prevented this elimination by binding to the inhibitory receptor signal regulatory Protein Alpha (SIRPAlpha). Thus, macrophages may use a number of nonspecific activating receptors and rely on the presence or absence of CD47 to distinguish self from foreign. CD47-SIRPAlpha may represent a potential pathway for the control of hemolytic anemia.