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. 2023 Feb 8;2(2):100082.
doi: 10.1016/j.jacig.2023.100082. eCollection 2023 May.

EP2 inhibition restores myeloid metabolism and reverses cognitive decline

Affiliations

EP2 inhibition restores myeloid metabolism and reverses cognitive decline

Ryan Lushington et al. J Allergy Clin Immunol Glob. .

Abstract

Nonsteroidal anti-inflammatory drugs alleviate pain and inflammation by inhibiting the cyclooxygenase pathway. This pathway has various downstream effects, some of which are beneficial. Prostaglandin E2 is a key downstream product in the cyclooxygenase pathway that modulates inflammation. A correlation between aging and increased expression of the prostaglandin E2 receptor, EP2, has been associated with inflammatory processes, cognitive aging, angiogenesis, and tumorigenesis. Therefore, inhibition of EP2 could lead to therapeutic effects and be more selective than inhibiting cyclooxygenase-2. Studies suggest that inhibition of EP2 restores age-associated spatial memory deficits and synaptic proteins and impairs tumorigenesis. The data indicate that EP2 signaling is important in myeloid cell metabolism and support its candidacy as a therapeutic target.

Keywords: COX; EP2; PGE2 signaling; cognition; cognitive decline; inflammation; myeloid metabolism; prostaglandin E2; tumorigenesis.

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Figures

Fig 1
Fig 1
G-protein–dependent signaling via β-catenin. A, Without the presence of an agonist for EP2, G-proteins remain inactive and β-catenin is phosphorylated and picked up by a nucleosome for destruction. At the same time, glycogen synthase I remains inactive and no glycogen is produced. B, The presence of PGE2 activates the αs guanosine triphosphate (GTP) subunit and releases β-catenin and GSK-3β from Axin. During this time, the free βγ subunits activate the PI3K-PDK1-AKT signaling pathway, resulting in the inhibitory phosphorylation of the free GSK-3β. GYS1 is then enabled to conduct glycogen synthesis without inhibition from GSK-3β. Without GSK-3β to inhibit it, the released β-catenin is allowed to undergo nuclear translocation, promoting gene expression and cell growth. AKT, Protein kinase B; APC, Adenomatous polyposis coli protein; CK1, casein kinase 1; GDP, guanosine diphosphate; GSK-3β, glycogen synthase kinase-3β; GYS1, glycogen synthase 1; LEF, lymphoid enchancer factor; PI3K, phosphoinositide 3-kinase; TCF, T-cell factor.
Fig 2
Fig 2
Two mechanisms converge, leading to bioenergetic insufficiency in myeloid cells. In aging myeloid cells, levels of PGE2 and EP2 are markedly increased. This increase leads to increased EP2 signaling, which subsequently leads to the activation of glycogen synthase 1 (GYS1), which decreases glucose flux. This culminates with metabolic changes in which myeloid cells become dependent on glucose energetically, resulting in a bioenergetics-deficient state. This bioenergetic state leads to the accumulation of proinflammatory mediators and harmful effects.
Fig 3
Fig 3
Myeloid knockdown of the EP2 receptor provides significant insight. The study conducted by Minhas et al using Cd11bCrelox/lox mice showed the effects of reducing EP2 expression by 50%. Notable impacts were the reduction in glycogen synthase 1 and the subsequent reduction in glycogen synthesis. Remarkably, physiological abnormalities observed within mitochondria associated with age reversed, indicating there is a connection between EP2 signaling and abnormalities in mitochondrial density, number, and morphology. GYS1, Glycogen synthase 1.

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