TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.
TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.
Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202;
Rui
R
Ji
Shifu
S
Tian
Helen J
HJ
Lu
Qingjun
Q
Lu
Yan
Y
Zheng
Xiaomin
X
Wang
Jixiang
J
Ding
Qiutang
Q
Li
Qingxian
Q
Lu
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004261:DNA Replication; D018891:Dentate Gyrus / Q000473:pathology*; D004660:Encephalitis / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051193:Toll-Like Receptors / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000093242:Interleukin-6 Inhibitors
D017077:Culture Media, Conditioned; D016207:Cytokines; D007213:Indomethacin; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051193:Toll-Like Receptors; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000093242:Interleukin-6 Inhibitors; C496317:Nos2 protein, mouse; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse