PGE ₂ signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia

Abstract

The inflammatory prostaglandin E2 (PGE 2 ) 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 PGE 2 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. PGE 2 | stroke | conditional knockout T he COX-1 and inducible COX-2 catalyze the first committed step in PGE 2 synthesis and function physiologically in the central nervous system to regulate synaptic plasticity, neurovascular coupling, and glial homeostasis. Of the five prostanoids downstream of COX-including PGE 2 , PGD 2 , PGF 2 α, prostacyclin, and thromboxane-PGE 2 has emerged as a unique modulator of disease-promoting neuronal and inflammatory processes. In pathologic contexts, induction of COX-2 in neurons and glia leads to generation of PGE 2 that signals through four G protein coupled receptors, EP1-EP4. In vivo studies of the EP receptor function using genetic knockout models have highlighted EP receptorspecific effects in a broad range of neurological disease models. For example, whereas the EP1 receptor elicits neurotoxic effects in models of cerebral ischemia (1), the EP4 receptor conversely mediates neuroprotective, vasodilatory, and antiinflammatory effects (2, 3). In models of familial Alzheimer's disease (AD), ablation of EP2 or EP3 receptors blunts inflammatory responses, amyloid accumulation, and loss of synaptic proteins (4-7), whereas deletion of microglial EP4 elicits the opposite (8). Thus, genetic studies demonstrate beneficial as well as detrimental PGE 2 EP signaling cascades that operate in receptor-specific ways.The PGE ...

Cyclooxygenase-1 mediates neuroinflammation and neurotoxicity in a mouse model of retinitis pigmentosa

“…More importantly, our finding raises the possibility that an EP2 antagonist could be used as a potential therapy to oppose neuroinflammation in RP. Consistent with our findings, EP2 deletion is reported to reduce inflammation and pathology in other neurodegenerative disorders [10][11][12]31]. The previous data together with our current findings suggest a general and critical role for EP2 receptor in neuroinflammation and neurodegeneration.…”

“…These results indicated that COX-1 deletion abrogated PGE2 elevation in the rd10 retina, suggesting that COX-1 primarily droved the observed increase in PGE2 in the rd10 retina. The receptor EP2, one of PGE2 downstream G-protein coupled receptors, is highly expressed in microglia in the brain [10][11][12]. To examine whether downregulation of PGE2 affected EP2 expression in the microglia of the COX-1 −/− / rd10 retina, we performed qPCR in sorted primary microglial cells by using flow cytometry.…”

Kellerin alleviates cognitive impairment in mice after ischemic stroke by multiple mechanisms

“…Moreover, for ischemic stroke patients, the effective therapeutic time window is approximately 4 hr (Shen et al, ). The inflammatory response lasts a long time after stroke onset, and anti‐inflammation therapy has been considered as a promising strategy in extending the therapeutic time window (Lambertsen et al, ; Liu et al, ; Shichita et al, ). The use of kellerin, a natural neuroinflammatory inhibitor, in overcoming the time window limitation in stroke therapy will potentially be of great clinical importance.…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…Moreover, pharmacological activation of EP2 by ONO-AE1-259-01 significantly reduced the infarct volume in mice (Ahmad et al, 2010). However, recent studies demonstrated that neuronal EP2-receptor expression is induced after cerebral ischemia (Liu et al, 2019). Validation of the anti-EP2 antibody used in that study was performed by using cerebellar lysates and HEK cells overexpressing the EP2 receptor.…”

“…Validation of the anti-EP2 antibody used in that study was performed by using cerebellar lysates and HEK cells overexpressing the EP2 receptor. The blockade of EP2 in mice contributed to cerebro-protection by reducing neuroinflammation (Liu et al, 2019), and EP2 knockout mice were shown to be more protected from intracerebral hemorrhage strokes (Leclerc et al, 2015b).…”