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

Grommes, Christian; Lee, C. Y. Daniel; Wilkinson, Brandy L.; Jiang, Qingguang; Koenigsknecht-Talboo, Jessica L.; Varnum, Brian; Landreth, Gary E.

doi:10.1007/s11481-007-9090-2

Cited by 162Phagocytosis and Immune RegulationNeuroinflammation and Neurodegeneration MechanismsCell death mechanisms and regulation

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

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Grommes, Christian, Lee, C. Y. Daniel, Wilkinson, Brandy L., Jiang, Qingguang, Koenigsknecht-Talboo, Jessica L., Varnum, Brian, Landreth, Gary E.·2008·Journal of Neuroimmune Pharmacology

DOI 10.1007/s11481-007-9090-2PMC PMC3653274

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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-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.

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Phagocytosis-related genes FCER1G, FCGR2A, TYROBP, and GAS6 are down-regulated in AD monocytes compared with AC monocytes, indicating a reduced ability of AD monocytes to phagocytose Aβ.
“We found that the expression of phagocytosis-related genes, including FCER1G, FCGR2A, TYROBP, and GAS6 (46–48), was down-regulated in AD monocytes as compared to AC monocytes (Fig. 3C), indicating a reduced ability of AD monocytes to phagocytose Aβ.”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [48]

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Authors: Grommes, C., Lee, C. Y. D., Wilkinson, B. L., Jiang, Q., Koenigsknecht-Talboo, J. L., Varnum, B., & Landreth, G. E.
Affiliations: Case Western Reserve University (US)
Washington University in St. Louis (US)
Amgen (United States) (US)
Corresponding author: Landreth, Gary E.
ORCID: Grommes, Christian
Wilkinson, Brandy L.
Landreth, Gary E.
Venue: Journal of Neuroimmune Pharmacology
Publisher: Springer Science and Business Media LLC
Published: 2007-10-10
Volume: 3
Issue: 2
Pages: 130-140
ISSN: 1557-1890 (ISSN-L)
1557-1904
DOI: 10.1007/s11481-007-9090-2
PMC: PMC3653274
OpenAlex: W2161966903
Cited by: 162
References: 56
Citations by year: 2026: 10 · 2025: 9 · 2024: 13 · 2023: 7 · 2022: 11 · 2021: 14 · 2020: 11 · 2019: 8 · 2018: 5 · 2017: 12 · 2016: 9 · 2015: 5 · 2014: 10 · 2013: 8 · 2012: 9
FWCI: 1.86
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Journal of Neuroimmune Pharmacology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Rockefeller Foundation
National Institute on Aging (AG-20202, R01AG020202, R01AG016740, AG-16740)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: Gas6, microglial phagocytosis, efferocytosis, Rac activation, anti-inflammatory response, IL-1β, inducible nitric oxide synthase, lipopolysaccharide, inflammatory gene expression, phosphatidylserine
MeSH terms: c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Animals, Brain, Cell Line, Cytoskeleton, Gene Expression Regulation, Inflammation, Lipopolysaccharides, Phagocytosis, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transcription, Genetic, Oncogene Proteins, Apoptosis, Microglia, rac GTP-Binding Proteins, Receptor Protein-Tyrosine Kinases, Intercellular Signaling Peptides and Proteins, Mice, Proto-Oncogene Proteins c-vav, Nitric Oxide Synthase Type II, Interleukin-1beta

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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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