文章基本信息

标题：PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia
本地全文：下载
作者：Qingkun Liu ; Qingkun Liu ; Xibin Liang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：20
页码：10019-10024
DOI：10.1073/pnas.1818544116
出版社：The National Academy of Sciences of the United States of America
摘要：The inflammatory prostaglandin E2 (PGE₂) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE₂ EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2^lox/lox mice attenuated brain infiltration of Cd11b⁺CD45^hi macrophages and CD45⁺Ly6G^hi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreER^T2 (ROSACreER);EP2^lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2^lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2^lox/lox mice, unlike EP2^−/− mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.
关键词：PGE₂ ; stroke ; conditional knockout