Journal Article

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

Gilchrist, Shannon E., Hafizi, Sassan, Pennelli, Grace M.

2021

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Alzheimer's disease / Animals / Antibodies / Antigens / Astrocytes / Axl protein / Brain - pathology / Cell culture / Cell Nucleus - metabolism / Cells, Cultured / Cerebrospinal fluid / Colony-stimulating factor / Cytokines / Gas6 / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Glial cells / GM-CSF / Granulocyte-macrophage colony-stimulating factor / Granulocyte-Macrophage Colony-Stimulating Factor - genetics / Granulocyte-Macrophage Colony-Stimulating Factor - metabolism / Inflammation / Inflammation - metabolism / Inflammation - pathology / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Kinases / Ligands / Lipopolysaccharides / Mice / Microglia / Microglia - metabolism / Microscopy / Neuronal-glial interactions / NF-kappa B - metabolism / NF-κB protein / Nuclear transport / Protein Transport / Protein-tyrosine kinase receptors / Protein-Tyrosine Kinases - metabolism / Proteins / RNA, Messenger - genetics / RNA, Messenger - metabolism / Signal Transduction / Synaptotagmin / TAM receptors / Toll-like receptors / Toll-Like Receptors - metabolism