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Gas6/TAM Signalling Negatively Regulates Inflammatory Induction of GM-CSF in Mouse Brain Microglia
Shannon E Gilchrist1, Grace M Pennelli1, Sassan Hafizi1
1School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK.
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.
Insights
Gas6 signaling significantly reduces the inflammatory response in microglia by suppressing granulocyte-macrophage colony-stimulating factor (GM-CSF) production. This pathway is crucial for regulating neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia and astrocytes are key glial cells in the central nervous system (CNS) mediating neuroinflammation.
- TAM receptors and Gas6 are known regulators of inflammatory responses, but their precise mechanisms in the CNS are unclear.
Purpose of the Study:
- To investigate how Gas6 modulates the inflammatory response of CNS glial cells, specifically microglia.
- To identify the molecular targets of Gas6 in the context of lipopolysaccharide (LPS)-induced inflammation.
Main Methods:
- Primary cultured mouse microglia were treated with LPS and Gas6.
- A qPCR array was used to analyze Toll-like receptor signaling pathway-associated genes.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) protein release was measured.
- Nuclear translocation of NF-κB p65 protein was assessed.
Main Results:
- Gas6 significantly blunted the LPS-induced upregulation of the Csf2 gene, which encodes GM-CSF.
- This suppression was confirmed at the protein level, with Gas6 inhibiting GM-CSF release.
- Microglia were identified as the primary CNS glial cell type responsive to LPS-induced GM-CSF production.
- Gas6 inhibited the LPS-stimulated nuclear translocation of NF-κB p65 in microglia.
Conclusions:
- Microglia are a major source of GM-CSF during CNS neuroinflammation.
- Gas6/TAM receptor signaling acts as a negative regulator of this neuroinflammatory response.
- Gas6 suppresses microglial GM-CSF production and NF-κB signaling, thereby mitigating neuroinflammation.
