Frontline Science: Reprogramming COX‐2, 5‐LOX, and CYP4A‐mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis

Abstract

Cyclooxygenase‐2 (COX‐2), 5‐lipoxygenase (5‐LOX), and cytochrome P450 (CYP) 4A‐mediated arachidonic acid (AA) metabolism play an essential role in human inflammatory disorders. Blocking COX‐2 pathway would shunt AA metabolism to the other pathway, thereby decreasing the efficacy and exacerbating adverse effects. Here we demonstrated that reprogramming COX‐2, 5‐LOX, and CYP4A‐mediated AA metabolism in macrophages by salidroside (Sal) ameliorates monosodium urate (MSU) crystal‐induced inflammation. Compared with COX‐2 inhibitor celecoxib, Sal (80 mg/kg) presented a superior anti‐arthritic profile in MSU crystal‐treated rats, accompanied with the decreased expression of COX‐2, 5‐LOX, and CYP4A and production of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and 20‐hydroxyeicosatetraenoic acid (20‐HETE) in the synovial fluid macrophages. Sal decreased representative M1 marker (iNOS and CD86, etc.) expression and M1 cytokine (TNF‐α and IL‐1β) production, whereas it increased M2 marker (CD206 and Arg‐1) expression and M2 cytokine (TGF‐β and IL‐10) production. The injection of conditioned medium from MSU crystal‐treated macrophages into the ankle joint of rats reproduced the gouty inflammation, which was attenuated by Sal. Mechanistically, down‐regulation of COX‐2, 5‐LOX, and CYP4A in the RAW264.7 and NR8383 macrophages by Sal skewed macrophage polarization away from the M1 phenotype, and thereby prevented neutrophil migration and chondrocyte degradation with STAT1 and NF‐κB inactivation. Conversely, overexpression of COX‐2, 5‐LOX, CYP4A or STAT1, or exogenous addition of IL‐1β or TNF‐α partially abolished these effects. Together, inhibition of COX‐2, 5‐LOX, and CYP4A in macrophages by Sal ameliorates MSU crystal‐induced inflammation through decreasing TNF‐α and IL‐1β production, and may serve as a novel therapeutic strategy.