Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we sh...Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we showed that lysophosphatidylserine(LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation.Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS.Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling.In vivo,reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke.Thus,our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation,and suggest it as a potential therapeutic target for demyelination-associated diseases.展开更多
基金supported by the National Key Research and Development Program of China(grant number 2020YFA0509101)the National Natural Science Foundation of China(grant numbers 81821001,82130107,U20A20359)the CAS Project for Young Scientists in Basic Research(YSBR-074).
文摘Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we showed that lysophosphatidylserine(LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation.Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS.Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling.In vivo,reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke.Thus,our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation,and suggest it as a potential therapeutic target for demyelination-associated diseases.
