TAM Receptors Affect Adult Brain Neurogenesis by Negative Regulation of Microglial Cell Activation

Abstract

TAM tyrosine kinases play multiple functional roles including regulation of the target genes important in homeostatic regulation of cytokine receptors or Toll-like receptor-mediated signal transduction pathways. Here, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impair hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAP kinase and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell (NSC) 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, e.g., IL-1β, IL-6, TNF-α, and iNOS, and this effect is antagonized by co-injection of the anti-inflammatory drug indomethacin in WT but not TKO brains. Conditioned medium from TKO microglia cultures inhibits NSC proliferation and neuronal differentiation. IL-6 knockout in Axl−/−Mertk−/− double knockout (DKO) 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. In addition, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promotes progenitor differentiation into immature neurons.

Zika Virus Infection: Current Concerns and Perspectives

“…As cutaneous fibroblasts and epidermal keratinocytes express AXL, this further supports the susceptibility of these cells to ZIKV infection. Astrocytes and microglial cells are known to have AXL and Tyro3 expression [75]. Therefore, astrocytes and microglial cell could be targets for ZIKV infection.…”

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

“…However, TAMs can also serve as co-receptors, such as for ␤5 integrin and interferon receptor (34). In this latter pathway, TAMs have been reported to stimulate phosphorylation of STAT1 acting as negative regulators of pro-inflammatory TLR-signaling and promoting the induction of suppressors of cytokine signaling SOCS-1 and SOCS-3 expression, which may in part explain why TAM(Ϫ/Ϫ) mice have elevated inflammatory cytokines such as IL-6 and TNF-␣ especially upon the activation of TLRs (35)(36)(37).…”

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

“…Therefore, the loss of these receptors disinhibits these processes and comprises neurogenesis in the dentate gyrus of the adult hippocampus, which leads to NSC proliferation, differentiation, and survival [32,33]. IL-6 is a major downstream neurotoxic mediator that is under the homeostatic regulation of TAM receptors in microglia [32]. Gas6 activates TAM receptors in adult neurogenesis, and knockout of Gas6 reduces the number of NSCs in the the subventricular zone of the lateral ventricles.…”

“…TAM receptors negatively affect microglia and peripheral antigen-presenting cells, inhibit MAPK and NF-κB activation and prevent the overproduction of pro-inflammatory cytokines. Therefore, the loss of these receptors disinhibits these processes and comprises neurogenesis in the dentate gyrus of the adult hippocampus, which leads to NSC proliferation, differentiation, and survival [32,33]. IL-6 is a major downstream neurotoxic mediator that is under the homeostatic regulation of TAM receptors in microglia [32].…”

“…Multipotent NSCs are located in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles in adult brain [31]. Neurogenesis is a dynamic process that is modulated by a variety of intrinsic and extrinsic factors, including growth factors, cell surface receptors, signal transduction molecules, transcriptional factors and cytokines/ chemokines [32,33].…”