Abstract：
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.
摘要：
无菌性神经炎症是多种神经系统疾病的主要驱动因素。髓磷脂碎片可以作为炎症刺激促进炎症和病理，但对其机制了解甚少。这里,我们发现溶血磷脂酰丝氨酸(LysoPS)-GPR34轴在小胶质细胞介导的髓鞘碎片感知和随后的神经炎症中起关键作用.髓鞘碎片诱导的小胶质细胞活化和促炎细胞因子表达依赖于其脂质成分LysoPS。髓鞘碎片和LysoPS均通过GPR34及其下游PI3K-AKT和ERK信号传导促进小胶质细胞活化和促炎细胞因子的产生。在体内,在多发性硬化症和中风的小鼠模型中,降低髓磷脂中的LysoPS含量或通过遗传或药理学方法抑制GPR34可减少神经炎症和病理。因此，我们的结果确定GPR34是感知脱髓鞘和中枢神经系统损伤并促进神经炎症的关键受体，并建议将其作为脱髓鞘相关疾病的潜在治疗靶点。
