GPR40 inhibits microglia-mediated neuroinflammation via the NLRP3/IL-1β/glutaminase pathway after subarachnoid hemorrhage

Subarachnoid hemorrhage is one type of strokes with high mortality and disability and there exists several mechanisms in SAH pathology. G-protein-coupled receptor 40 (GPR40) is proven to exert anti-inflammatory effects in several central nervous system (CNS) diseases. However, the precise role of GPR40 in SAH pathogenesis remains largely unknown. In this study, both in vivo and in vitro SAH models were used to investigate the mechanism of GPR40 attenuating neuroinflammation after SAH onset. We found that GPR40 expression in microglia decreased, which promoted IL-1β secretion and aggravated neuronal death after SAH onset. The GPR40 agonist GW9508 attenuated neuronal damage and ameliorated neurological deficits in SAH-model mice. Mechanistically, GPR40 in microglia inhibited pyroptosis, and cytokine production via inhibiting NLRP3/caspase-1/IL-1β pathway. Then the level of IL-1β secreted by microglia and transported to neurons via exosome were decreased, which down-regulated glutaminase, counteracted glutamate accumulation, and facilitated neuronal survival. These results revealed that GPR40 is a novel regulator that inhibits microglia-mediated neuroinflammation and is a potential therapeutic target in SAH therapy.