TAM receptors regulate multiple features of microglial physiology
Open accessAbstract
Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.
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Activation of the tyrosine kinase of TAM receptors upon ligand binding recruits the p85 subunit of PI3K and activates PI3K/Akt signaling.
“Activation of the tyrosine kinase of TAM receptors upon ligand binding recruits the p85 subunit of PI3K and activates PI3K/Akt signaling [147–150].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [149]
The Abstract identifies TAM receptors as tyrosine kinases and says their ligands drive microglial phagocytosis. Neither it nor the additional passages retrieved for “p85 subunit of PI3K” and “PI3K Akt signaling ligand binding phosphorylation” addresses p85 recruitment or PI3K/Akt activation, so the attributed signaling mechanism cannot be verified from our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe detrimental role of microglia in alpha-synuclein pathology may be mediated by the phagocytic receptor Axl.
“A recent study has indicated that the detrimental role of microglia in α-synuclein pathology may be mediated by the phagocytic receptor Axl (23).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [23]
Microglia use nearly 100 genes, their sensome, to detect microenvironment changes; this includes P2yr12, AXL, and MER.
“They use the products of nearly 100 genes to sense changes in their microenvironment (their sensome) including P2yr12, AXL, and MER4,7,19”
From Microglia in neurodegeneration (2018) · cites this paper as [19]
Microglia contribute to neurogenesis through phagocytosis of excessive newborn cells and by promoting neurogenesis through cytokine secretion, and phagocytosis depends on MERTK.
“Microglia contribute to neurogenesis in two ways: through phagocytosis of excessive newborn cells and by promoting neurogenesis through the secretion of cytokines.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
Microglial activation acts through TAM (TYRO3, AXL and MERTK)-dependent mechanisms to have a detrimental role in a mouse model of Parkinson disease.
“Microglial activation appears to act via TAM (TYRO3, AXL and MERTK)-dependent mechanisms to have a detrimental role in a mouse model of PD106.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
TAM receptors are involved in multiple aspects of microglial physiology.
“TAM receptors are involved in multiple aspects of microglial physiology106.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
Animals deficient in Mer and Axl accumulate apoptotic cells.
“Animals deficient in Mer and Axl accumulate apoptotic cells106.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
These functions are regulated by the TAM receptor tyrosine kinases MER and AXL.
“These functions are regulated by the TAM receptor tyrosine kinases MER and AXL.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
MERTK on microglia is required for clearing apoptotic cells in the neurogenic regions of the CNS.
“This study shows that microglial MERTK is essential for elimination of apoptotic cells in neurogenic regions of the CNS.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [106]
AXL/MERTK deficiency results in accumulation of apoptotic cCASP3+ cells in the cerebellum of adult mice.
“We found that AXL/MERTK deficiency results in the accumulation of apoptotic cCASP3+ cells in the cerebellum of adult mice (Fig. 3b), suggesting that the presence of dying cells is not caused by the loss of microglia but reflects the attenuation of microglia clearance function.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [25]
Most newly generated neurons/T-cells undergo apoptotic cell death, and dying cells cannot be readily detected due to rapid removal by resident macrophages/microglia.
“While most of the newly generated neurons/T-cells undergo apoptotic cell death, the dying cells cannot be readily detected due to their rapid removal by resident macrophages/microglia25,39.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [25]
Microglia can sense and clear apoptotic cells at the earliest stages of apoptosis.
“Recent evidence suggests that microglia can sense and clear apoptotic cells at the earliest stages of apoptosis25.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [25]
The rapid microglia-mediated removal of dying neurons in the subventricular zone and apoptotic thymocytes during T-cell development is compatible with the observed scenario.
“This scenario is compatible with the rapid microglia-mediated removal of dying neurons in the subventricular zone25 as well as apoptotic thymocytes during T-cell development39.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [25]
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References 39 · Cited by 600
Research works printed but not linked: 7
- [33]Burstyn-Cohen T Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis Neuron 2012 76 1123 1132 23259948 PMC3530147
- [34]Jung S Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion Mol Cell Biol 2000 20 4106 4114 10805752 PMC85780
- [35]Parkhurst CN Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor Cell 2013 155 1596 1609 24360280 PMC4033691
- [37]Chandra S Gallardo G Fernandez-Chacon R Schluter OM Sudhof TC Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration Cell 2005 123 383 396 16269331
- [38]Zagórska A Través PG Lew ED Dransfield I Lemke G Diversification of TAM receptor tyrosine kinase function Nat Immunol 2014 15 920 928 25194421 PMC4169336
- [39]Lew ED Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities eLife 2014 3 e03385 PMC4206827 25265470
- [46]Nimmerjahn A Kirchhoff F Helmchen F Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 2005 308 1314 1318 15831717
- Authors
- Fourgeaud, L., Través, P. G., Tufail, Y., Leal-Bailey, H., Lew, E. D., Burrola, P. G., Callaway, P., Zagórska, A., Rothlin, C. V., Nimmerjahn, A., & Lemke, G.
- Affiliations
- Salk Institute for Biological Studies (US)
- Yale University (US)
- Corresponding author
- Rothlin, Carla V.
- Lemke, Greg
- ORCID
- Venue
- Nature
- Published
- 2016-04
- Volume
- 532
- Issue
- 7598
- Pages
- 240-244
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5358512
- OpenAlex
- W2333008150
- Cited by
- 600
- References
- 39
- Citations by year
- 2026: 48 · 2025: 51 · 2024: 65 · 2023: 46 · 2022: 77 · 2021: 80 · 2020: 66 · 2019: 57 · 2018: 43 · 2017: 47 · 2016: 18
- FWCI
- 30.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Hearst Foundations
- Leona M. and Harry B. Helmsley Charitable Trust
- National Cancer Institute (P30CA014195)
- National Institute of Allergy and Infectious Diseases (R01AI101400, R01AI089824)
- National Institute of Neurological Disorders and Stroke (R01NS085296, DP2NS083038, R01NS085938, R01NS110688)
- National Center for Chronic Disease Prevention and Health Promotion (DP2 NS083038)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- TAM receptors, Mer receptor, AXL receptor, microglia, phagocytosis, efferocytosis, neurogenic niche, adult neurogenesis, Gas6, protein S, brain injury response, Parkinson's disease, neuroinflammation, receptor tyrosine kinase
- MeSH terms
- c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Growth Arrest-Specific Protein 6, Animals, Brain, Brain Injuries, Disease Models, Animal, Female, Inflammation, Ligands, Male, Parkinson Disease, Phagocytosis, Proto-Oncogene Proteins, Signal Transduction, Up-Regulation, Apoptosis, Protein S, Microglia, Receptor Protein-Tyrosine Kinases, Intercellular Signaling Peptides and Proteins, Mice, Stem Cell Niche, Neurogenesis
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