Gas6/TAM Signalling Negatively Regulates Inflammatory Induction of GM-CSF in Mouse Brain Microglia

Abstract

Microglia and astrocytes are the main CNS glial cells responsible for the neuroinflammatory response, where they release a plethora of cytokines into the CNS inflammatory milieu. The TAM (Tyro3, Axl, Mer) receptors and their main ligand Gas6 are regulators of this response, however, the underlying mechanisms remain to be determined. We investigated the ability of Gas6 to modulate the CNS glial inflammatory response to lipopolysaccharide (LPS), a strong pro-inflammatory agent, through a qPCR array that explored Toll-like receptor signalling pathway-associated genes in primary cultured mouse microglia. We identified the Csf2 gene, encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), as a major Gas6 target gene whose induction by LPS was markedly blunted by Gas6. Both the Csf2 gene induction and the suppressive effect of Gas6 on this were emulated through measurement of GM-CSF protein release by cells. We found distinct profiles of GM-CSF induction in different glial cell types, with microglia being most responsive during inflammation. Also, Gas6 markedly inhibited the LPS-stimulated nuclear translocation of NF-κB p65 protein in microglia. These results illustrate microglia as a major resident CNS cellular source of GM-CSF as part of the neuroinflammatory response, and that Gas6/TAM signalling inhibits this response through suppression of NF-κB signalling.

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

“…GAS6 is a ligand for the tyrosine kinase receptors TYRO3, AXL and MERTK (TAM) that stimulate microglial phagocytosis (94). Its signalling is also known to dampen the LPS inflammatory response of primary cultured microglia (95), mediated by TGF-β expression (96), which was increased in ELS microglia. GAS6 is present at high levels in the brain throughout development, continues to be expressed in adulthood in rodents and humans (56,97), and may act as a neurotrophic factor for hippocampal neurons (98).…”

“…An additional significance of the hippocampal GAS6-TAM pathway is its dual role in regulating neurogenesis both directly by supporting neural stem cells, and indirectly by inhibiting microglia and astrocytes (95). Given the ample evidence of long-term modulation of adult hippocampal neurogenesis by ELS (104), there might be clinical implications for targeting TAM receptor-mediated signalling pathways to treat conditions accompanied by neurogenesis loss (100,105), such as depression (101), for which ELS is a major risk factor (3).…”

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

“…Study has been shown that blockade of CSF2 signaling reduces airway inflammation and hyperresponsiveness in mouse models of environmentally induced lung injury and asthma ( Burkhardt et al., 2012 ; Gilchrist et al., 2021 ). Lung tissue-resident memory-like TH17 cells are predominant immune cell type in bronchoalveolar lavage fluid (BAL) expressing the cytokine GM-CSF.…”

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

“…GAS6 is a ligand for the tyrosine kinase receptors TYRO3, AXL and MERTK (TAM) that stimulate microglial phagocytosis (94). Its signalling is also known to dampen the LPS in ammatory response of primary cultured microglia (95), mediated by TGF-β expression (96), which was increased in ELS microglia. GAS6 is present at high levels in the brain throughout development, continues to be expressed in adulthood in rodents and humans (56,97), and may act as a neurotrophic factor for hippocampal neurons (98).…”

“…An additional signi cance of the hippocampal GAS6-TAM pathway is its dual role in regulating neurogenesis both directly by supporting neural stem cells, and indirectly by inhibiting microglia and astrocytes (95). Given the ample evidence of long-term modulation of adult hippocampal neurogenesis by ELS (104), there might be clinical implications for targeting TAM receptor-mediated signalling pathways to treat conditions accompanied by neurogenesis loss (100,105), such as depression (101), for which ELS is a major risk factor (3).…”