PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia

Abstract

Significance Stroke is the leading cause of disability and fifth leading cause of mortality in the United States. Previous studies demonstrate a highly protective effect of inhibiting cyclooxygenase-2 (COX-2) after stroke, indicating that downstream PGE2 signaling pathways cause cerebral ischemic injury. Using conditional knockout strategies to study the role of PGE2 EP2 signaling in a model of cerebral ischemia, we determine that neuronal EP2 signaling, which is highly induced following cerebral ischemia, increases cerebral injury. We demonstrate that EP2 blockade in adult mice is highly cerebroprotective and myeloid EP2 signaling increases the poststroke innate immune response. Additionally, the present results differ from previous studies of congenitally null EP2 mice, reflecting a potential confounding effect of congenital deletion of EP2. 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;EP2lox/lox mice attenuated brain infiltration of Cd11b+CD45hi macrophages and CD45+Ly6Ghi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreERT2 (ROSACreER);EP2lox/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;EP2lox/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;EP2lox/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.