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

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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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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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Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827
Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · cited 5×
“An important adaptive characteristic of apoptosis is that cells are removed from the organism by macrophages through a highly specialized process in which the apoptotic cell does not elicit an immune response (Fadok et al. 1998; Voll et al. 1997).”
BackgroundInfluential
Mechanisms of phagocytosis in macrophages
Aderem, A., & Underhill, D. M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.593 · Cited by 2,854
Immunosuppressive effects of apoptotic cells
Voll, R. E., Herrmann, M., Roth, E. A., Stach, C., Kalden, J. R., & Girkontaite, I. (1997) · Nature · doi:10.1038/37022 · Cited by 1,787
Dissecting temporal and spatial control of cytokinesis with a myosin II Inhibitor
Straight, A. F., Cheung, A., Limouze, J., Chen, I., Westwood, N. J., Sellers, J. R., & Mitchison, T. J. (2003) · Science · doi:10.1126/science.1081412 · Cited by 1,412
Phagocytosis and clearance of apoptotic cells is mediated by MER
Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., & Matsushima, G. K. (2001) · Nature · doi:10.1038/35075603 · Cited by 1,215
Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124
Microglia and neuroinflammation: a pathological perspective
Streit (2004) · Journal of Neuroinflammation · doi:10.1186/1742-2094-1-14 · Cited by 1,039
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases
Caron, E., & Hall, A. (1998) · Science · doi:10.1126/science.282.5394.1717 · Cited by 1,019
Genes specifically expressed at growth arrest of mammalian cells
Schneider, C., King, R. M., & Philipson, L. (1988) · Cell · doi:10.1016/s0092-8674(88)91065-3 · Cited by 989
Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat
D'Cruz, P. M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.4.645 · Cited by 884
Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta.
Lee, S. C., Liu, W., Dickson, D. W., Brosnan, C., & Berman, J. (1993) · Journal of Immunology · doi:10.4049/jimmunol.150.7.2659 · Cited by 850
The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases
Stitt, T. N., Conn, G., Goret, M., Lai, C., Bruno, J., Radzlejewski, C., Mattsson, K., Fisher, J., Gies, D. R., Jones, P. F., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90520-0 · Cited by 733
β-Amyloid Stimulation of Microglia and Monocytes Results in TNFα-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis
Combs, C. K., Karlo, J. C., Kao, S.-C., & Landreth, G. E. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01179.2001 · Cited by 721
Self-citation
Homeostatic Regulation of the Immune System by Receptor Tyrosine Kinases of the Tyro 3 Family
Lu, Q., & Lemke, G. (2001) · Science · doi:10.1126/science.1061663 · Cited by 699
Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases*
Nagata, K., Ohashi, K., Nakano, T., Arita, H., Zong, C., Hanafusa, H., & Mizuno, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.30022 · Cited by 541
Tyro-3 family receptors are essential regulators of mammalian spermatogenesis
Lu, Q., Gore, M., Zhang, Q., Camenisch, T., Boast, S., Casagranda, F., Lai, C., Skinner, M. K., Klein, R., Matsushima, G. K., et al. (1999) · Nature · doi:10.1038/19554 · Cited by 514
Apoptotic cell removal
Henson, P. M., Bratton, D. L., & Fadok, V. A. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00474-2 · Cited by 485
Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase
Bratton, D. L., Fadok, V. A., Richter, D., Kailey, J. M., Guthrie, L. A., & Henson, P. M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.42.26159 · Cited by 485
Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6
Varnum, B. C., Young, C., Elliott, G., Garcia, A., Bartley, T. D., Fridell, Y.-W. C., Hunt, R. W., Trail, G., Clogston, C., Toso, R. J., et al. (1995) · Nature · doi:10.1038/373623a0 · Cited by 482
Self-citation
Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism
Koenigsknecht-Talboo, J., & Landreth, G. E. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2557-04.2004 · Cited by 457
Self-citation
Fibrillar β-Amyloid Induces Microglial Phagocytosis, Expression of Inducible Nitric Oxide Synthase, and Loss of a Select Population of Neurons in the Rat CNS In Vivo
Weldon, D. T., Rogers, S. D., Ghilardi, J. R., Finke, M. P., Cleary, J. P., O’Hare, E., Esler, W. P., Maggio, J. E., & Mantyh, P. W. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-06-02161.1998 · Cited by 348
Phosphatidylserine recognition by phagocytes: a view to a kill
Wu, Y., Tibrewal, N., & Birge, R. B. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.02.003 · Cited by 341
Recognition and phagocytosis of cells undergoing apoptosis
Savill, J. (1997) · British Medical Bulletin · doi:10.1093/oxfordjournals.bmb.a011626 · Cited by 331
A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock.
Camenisch, T. D., Koller, B. H., Earp, H. S., & Matsushima, G. K. (1999) · PubMed · Cited by 321
VAV proteins as signal integrators for multi-subunit immune-recognition receptors
Turner, M., & Billadeau, D. D. (2002) · Nature reviews. Immunology · doi:10.1038/nri840 · Cited by 320
A Novel Receptor Tyrosine Kinase, Mer, Inhibits TNF-α Production and Lipopolysaccharide-Induced Endotoxic Shock
Camenisch, T. D., Koller, B. H., Earp, H. S., & Matsushima, G. K. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.6.3498 · Cited by 290
A Requirement for the Rho-Family GTP Exchange Factor Vav in Positive and Negative Selection of Thymocytes
Turner, M., Mee, P. J., Walters, A. E., Quinn, M. E., Mellor, A. L., Zamoyska, R., & Tybulewicz, V. L. J. (1997) · Immunity · doi:10.1016/s1074-7613(00)80367-2 · Cited by 283
Cell Adhesion to Phosphatidylserine Mediated by a Product of Growth Arrest-specific Gene 6*
Nakano, T., Ishimoto, Y., Kishino, J., Umeda, M., Inoue, K., Nagata, K., Ohashi, K., Mizuno, K., & Arita, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.47.29411 · Cited by 264
Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts.
Goruppi, S., Ruaro, E. M., & Schneider, C. (1996) · PubMed · Cited by 262
Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6.
Ishimoto, Y., Ohashi, K., Mizuno, K., & Nakano, T. (2000) · Journal of Biochemistry (Tokyo) · doi:10.1093/oxfordjournals.jbchem.a022622 · Cited by 248
Rho-Kinase and Myosin-II Control Phagocytic Cup Formation during CR, but Not FcγR, Phagocytosis
Olazabal, I. M., Caron, E., May, R. C., Schilling, K., Knecht, D. A., & Machesky, L. M. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01069-2 · Cited by 237
Vav proteins, adaptors and cell signaling
Bustelo, X. R. (2001) · Oncogene · doi:10.1038/sj.onc.1204780 · Cited by 211
Tyrosine phosphorylation is required for Fc receptor–mediated phagocytosis in mouse macrophages
Greenberg, S., Chang, P., & Silverstein, S. C. (1993) · The Journal of experimental medicine · doi:10.1084/jem.177.2.529 · Cited by 198
Innate Immune Discrimination of Apoptotic Cells: Repression of Proinflammatory Macrophage Transcription Is Coupled Directly to Specific Recognition
Cvetanović, M., & Ucker, D. S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.2.880 · Cited by 191
Signal transduction of phagocytosis
Greenberg, S. (1995) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)88957-6 · Cited by 180
p38 MAPK-mediated Transcriptional Activation of Inducible Nitric-oxide Synthase in Glial Cells
Bhat, N. R., Feinstein, D. L., Shen, Q., & Bhat, A. N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204994200 · Cited by 179
The phagocytosis of apoptotic cells
Fadok, V. A., & Chimini, G. (2001) · Seminars in Immunology · doi:10.1006/smim.2001.0333 · Cited by 166
Macrophage regulation by Tyro 3 family receptors
Lemke, G., & Lu, Q. (2003) · Current Opinion in Immunology · doi:10.1016/s0952-7915(02)00016-x · Cited by 159
Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells
Hasanbasic, I., Cuerquis, J., Varnum, B., & Blostein, M. D. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00020.2004 · Cited by 156
Self-citation
“Recruitment Signals” from Apoptotic Cells
Ravichandran, K. S. (2003) · Cell · doi:10.1016/s0092-8674(03)00471-9 · Cited by 154
Chemoattractant-Stimulated Rac Activation in Wild-Type and Rac2-Deficient Murine Neutrophils: Preferential Activation of Rac2 and Rac2 Gene Dosage Effect on Neutrophil Functions
Li, S., 山内, 明., Marchal, C. C., Molitoris, J. K., Quilliam, L. A., & Dinauer, M. C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.5043 · Cited by 150
Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells
Hall, M. O., Obin, M. S., Heeb, M. J., Burgess, B. L., & Abrams, T. A. (2005) · Experimental Eye Research · doi:10.1016/j.exer.2005.03.017 · Cited by 145
Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells
Hirt, U. A., & Leist, M. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401286 · Cited by 138
Modular components of phagocytosis
Greenberg, S. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.5.712 · Cited by 137
Fibrillar β-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia
Wilkinson, B. L., Koenigsknecht-Talboo, J., Grommes, C., Lee, C. Y. D., & Landreth, G. E. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600627200 · Cited by 131
Self-citation
Signaling and invasin-promoted uptake via integrin receptors
Isberg, R. R., Hamburger, Z. A., & Dersch, P. (2000) · Microbes and Infection · doi:10.1016/s1286-4579(00)90364-2 · Cited by 122
Differential requirements for cellular cytoskeleton in human macrophage complement receptor- and Fc receptor-mediated phagocytosis
Newman, S. L., Mikus, L. K., & Tucci, M. A. (1991) · The Journal of Immunology · doi:10.4049/jimmunol.146.3.967 · Cited by 116
Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system1Published on the World Wide Web on 2 December 1998.1
Prieto, A. L., Weber, J. L., Tracy, S., Heeb, M. J., & Lai, C. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01159-7 · Cited by 116
An SH2 Domain-dependent, Phosphotyrosine-independent Interaction between Vav1 and the Mer Receptor Tyrosine Kinase
Mahajan, N. P., & Earp, H. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305817200 · Cited by 107
Apoptosis: giving phosphatidylserine recognition an assist – with a twist
Fadok, V. A., & Henson, P. M. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00575-x · Cited by 95
Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons
Funakoshi, H., Yonemasu, T., Nakano, T., Matumoto, K., & Nakamura, T. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10211 · Cited by 92
Gas6 rescues cortical neurons from amyloid β protein-induced apoptosis
Yagami, T. (2002) · Neuropharmacology · doi:10.1016/s0028-3908(02)00333-7 · Cited by 92
The clearance of apoptotic cells: implications for autoimmunity
Pittoni, V. (2002) · Autoimmunity Reviews · doi:10.1016/s1568-9972(02)00032-0 · Cited by 76
Differential effects of NGF and NT-3 on embryonic trigeminal axon growth patterns
Ulupınar, E., Jacquin, M. F., & Erzurumlu, R. S. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20000918)425:2 · Cited by 52
Effect of Gas6 on secretory phospholipase A2-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. (2003) · Brain Research · doi:10.1016/s0006-8993(03)03043-9 · Cited by 24

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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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