Lactate reprograms PGE2 metabolism via GPR81 inhibits COX2 to relieved psoriasis.

Psoriasis is an autoimmune skin disease whose precise pathogenesis remains incompletely understood. This study uncovered a critical role of lactate-induced metabolic reprogramming via GPR81 in the development of imiquimod-induced murine psoriasis. The activation of the lactate receptor GPR81 was found to be essential for reducing prostaglandin E2 (PGE2), a known lipid marker associated inflammation. GPR81 knockout (GPR81⁻/⁻) mice exhibited elevated PGE2 levels in epidermis, further supporting PGE2 as a metabolic indicator of psoriasis and suggesting its role in disease exacerbation. Similarly, treatment with reserpine, a newly identified GPR81 inhibitor, led to increased PGE2 levels compared to the control group. Mechanistically, inhibition of GPR81 upregulated cyclooxygenase-2 (COX-2), a rate-limiting enzyme in PGE2 synthesis. Moreover, GPR81⁻/⁻ mice displayed enhanced immune cell activation and proliferation relative to wild-type (WT) mice, including a marked increase in M1-polarized macrophages, elevated CD8⁺ and CD4⁺ T cell populations, and heightened secretion of pro-inflammatory cytokines such as IL-17, IL-23, and TNF-α. These alterations were associated with aggravated dermatological manifestations, including pronounced scaling, epidermal hyperplasia, and inflammatory cell infiltration accompanied by elevated cytokine production. Conversely, administration of the GPR81 agonist 3,5-Dihydroxybenzoic Acid (3,5-DHBA) significantly suppressed COX-2 expression and PGE2 levels by inhibiting PKA activation, thereby alleviating psoriatic symptoms. Collectively, these findings reveal a novel mechanism whereby GPR81 reprograms PGE2 synthesis through PKA-mediated downregulation of COX-2, highlighting GPR81 as a promising therapeutic target. The use of 3,5-DHBA demonstrates significant therapeutic potential for the treatment of autoimmune disease.