Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1)

Background Uterine inflammatory processes trigger prolabor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve postpartum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81in the uterusto exert in a feedback manner antiinflammatory effects, to resolve or mitigate inflammation. Objective We sought to investigate the role of lactate produced during labor and its receptor, GPR81, in regulating inflammation in the uterus. Study Design We investigated the expression of GPR81in the uterusand the pharmacological role of lactate acting via GPR81during labor, using shRNA- GPR81and GPR81–/– mice. Results (1) Uterine lactate levels increased substantially from 2 to 9 mmol/L during labor. (2) Immunohistological analysis revealed expression of GPR81in the uteruswith high expression in myometrium. (3) GPR81expression increased during gestation, and peaked near labor. (4) In primary myometrial smooth muscle cell and ex vivo uteri from wild-type mice, lactate decreased interleukin-1β-induced transcription of key proinflammatory Il1b , Il6 , Ccl2, and Pghs2 ; suppressive effects of lactate were not observed in cells and tissues from GPR81–/– mice. (5) Conversely, proinflammatory gene expression was augmented in the uterusat term in GPR81–/– mice and wild-type mice treated intrauterine with lentiviral-encoded shRNA- GPR81; GPR81silencing also induced proinflammatory gene transcription in the uteruswhen labor was induced by endotoxin (lipopolysaccharide). (6) Importantly, administration to pregnant mice of a metabolically stable specific GPR81agonist, 3,5-dihydroxybenzoic acid, decreased endotoxin-induced uterine inflammation, preterm birth, and associated neonatal mortality. Conclusion Collectively, our data uncover a novel link between the anaerobic glycolysisand the control of uterine inflammation wherein the high levels of lactate produced during labor act on uterine GPR81to down-regulate key proinflammatory genes. This discovery may represent a novel feedback mechanism to regulate inflammation during labor, and conveys a potential rationale for the use of GPR81agonists to attenuate inflammation and resulting preterm birth.