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

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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.

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Acknowledgments

We would like to thank Dr. Hugh Perry for his constructive discussions leading to this work. We thank Dr. N. Bhat (Medical University of South Carolina) for providing us with the iNOS reporter construct. This work was supported by grants from the NIH (AG-20202 and AG-16740) and the Blanchette Hooker Rockefeller Foundation.

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Authors and Affiliations

  1. Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH, 44106, USA

    Christian Grommes, C. Y. Daniel Lee, Brandy L. Wilkinson, Qingguang Jiang & Gary E. Landreth

  2. School of Medicine, Department of Neurology, Washington University, St. Louis, MO, 63130, USA

    Jessica L. Koenigsknecht-Talboo

  3. Amgen, Inc., De Havilland Drive, Thousand Oaks, CA, 91320, USA

    Brian Varnum

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  1. Christian Grommes
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  2. C. Y. Daniel Lee
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Correspondence to Gary E. Landreth.

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Grommes, C., Lee, C.Y.D., Wilkinson, B.L. et al. Regulation of Microglial Phagocytosis and Inflammatory Gene Expression by Gas6 Acting on the Axl/Mer Family of Tyrosine Kinases. J Neuroimmune Pharmacol 3, 130–140 (2008). https://doi.org/10.1007/s11481-007-9090-2

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