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Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases

Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the... Removal of apoptotic cells is an essential process for normal development and tissue maintenance. Importantly, apoptotic cells stimulate their phagocytosis by macrophages while actively suppressing inflammatory responses. Growth arrest specific gene 6 (Gas6) is involved in this process, bridging phosphatidylserine residues on the surface of apoptotic cells to the Axl/Mer family of tyrosine kinases which stimulate phagocytosis. Animals with mutations or loss of these receptors exhibit phenotypes reflective of impaired phagocytosis and a hyperactive immune response. We report that Gas6 induces phagocytosis in microglia through a novel non-classical phagocytic mechanism. Gas6 stimulates a type-II-related phagocytic response, but requires Vav phosphorylation and Rac activation, distinguishing it from the classical type II mechanism. Importantly, Gas6 suppressed lipopolysaccharide-induced expression of the inflammatory molecules IL-1β and iNOS. Gas6 inhibited iNOS expression through suppression of promoter activity. The present data provide direct evidence for the role of Gas6 receptors in mediating an anti-inflammatory response to ligands found on apoptotic cells with the simultaneous stimulation of phagocytosis. These data provide a mechanistic explanation for the phenotype observed in animals lacking Axl/Mer receptors. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neuroimmune Pharmacology Springer Journals

Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases

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Publisher
Springer Journals
Copyright
Copyright © 2007 by Springer Science+Business Media, LLC
Subject
Biomedicine; Cell Biology; Virology ; Pharmacology/Toxicology ; Immunology; Neurosciences
ISSN
1557-1890
eISSN
1557-1904
DOI
10.1007/s11481-007-9090-2
pmid
18247125
Publisher site
See Article on Publisher Site

Abstract

Removal of apoptotic cells is an essential process for normal development and tissue maintenance. Importantly, apoptotic cells stimulate their phagocytosis by macrophages while actively suppressing inflammatory responses. Growth arrest specific gene 6 (Gas6) is involved in this process, bridging phosphatidylserine residues on the surface of apoptotic cells to the Axl/Mer family of tyrosine kinases which stimulate phagocytosis. Animals with mutations or loss of these receptors exhibit phenotypes reflective of impaired phagocytosis and a hyperactive immune response. We report that Gas6 induces phagocytosis in microglia through a novel non-classical phagocytic mechanism. Gas6 stimulates a type-II-related phagocytic response, but requires Vav phosphorylation and Rac activation, distinguishing it from the classical type II mechanism. Importantly, Gas6 suppressed lipopolysaccharide-induced expression of the inflammatory molecules IL-1β and iNOS. Gas6 inhibited iNOS expression through suppression of promoter activity. The present data provide direct evidence for the role of Gas6 receptors in mediating an anti-inflammatory response to ligands found on apoptotic cells with the simultaneous stimulation of phagocytosis. These data provide a mechanistic explanation for the phenotype observed in animals lacking Axl/Mer receptors.

Journal

Journal of Neuroimmune PharmacologySpringer Journals

Published: Oct 10, 2007

References

  • Mechanisms of phagocytosis in macrophages
    Aderem, A; Underhill, DM
  • Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat
    D’Cruz, PM; Yasumura, D; Weir, J; Matthes, MT; Abderrahim, H; LaVail, MM; Vollrath, D
  • Apoptosis: giving phosphatidylserine recognition an assist-with a twist
    Fadok, VA; Henson, PM
  • Tyrosine phosphorylation is required for Fc receptor-mediated phagocytosis in mouse macrophages
    Greenberg, S; Chang, P; Silverstein, SC
  • Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells
    Hasanbasic, I; Cuerquis, J; Varnum, B; Blostein, MD
  • Apoptotic cell removal
    Henson, PM; Bratton, DL; Fadok, VA
  • Macrophage regulation by Tyro 3 family receptors
    Lemke, G; Lu, Q
  • The clearance of apoptotic cells: implications for autoimmunity
    Pittoni, V; Valesini, G
  • Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system
    Prieto, AL; Weber, JL; Tracy, S; Heeb, MJ; Lai, C
  • Recognition and phagocytosis of cells undergoing apoptosis
    Savill, J
  • Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2
    Takahashi, K; Rochford, CD; Neumann, H
  • Effect of Gas6 on secretory phospholipase A(2)-IIA-induced apoptosis in cortical neurons
    Yagami, T; Ueda, K; Asakura, K; Okamura, N; Sakaeda, T; Sakaguchi, G; Itoh, N; Hashimoto, Y; Nakano, T; Fujimoto, M

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