Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases
| Autor: | Christian Grommes, Gary E. Landreth, Brandy L. Wilkinson, C. Y. Daniel Lee, Jessica Koenigsknecht-Talboo, Brian Varnum, Qingguang Jiang |
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| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
Transcription Genetic Recombinant Fusion Proteins Phagocytosis Interleukin-1beta Immunology Neuroscience (miscellaneous) Nitric Oxide Synthase Type II Apoptosis C-Mer Tyrosine Kinase Biology Article Cell Line Mice Proto-Oncogene Proteins medicine Animals Immunology and Allergy Phosphorylation Proto-Oncogene Proteins c-vav Cytoskeleton Inflammation Oncogene Proteins Pharmacology Regulation of gene expression c-Mer Tyrosine Kinase Microglia GAS6 Brain Receptor Protein-Tyrosine Kinases Axl Receptor Tyrosine Kinase rac GTP-Binding Proteins Cell biology Rac GTP-Binding Proteins medicine.anatomical_structure Gene Expression Regulation Intercellular Signaling Peptides and Proteins Protein Processing Post-Translational Tyrosine kinase |
| Zdroj: | Journal of Neuroimmune Pharmacology. 3:130-140 |
| ISSN: | 1557-1904 1557-1890 |
| DOI: | 10.1007/s11481-007-9090-2 |
| Popis: | 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-1beta 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. |
| Databáze: | OpenAIRE |
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