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Macrophage COX‐2/mPGES‐1/PGE2 mediates inflammatory pain in peripheral tissues

Nonsteroidal anti‐inflammatory drugs (NSAIDs) alleviate inflammatory pain by inhibiting prostanoid formation, but are associated with serious cardiovascular and gastrointestinal adverse effects. Identification of the dominant tissue sources of prostanoid formation may lead to more targeted therapeutic approaches. We studied the contribution of macrophage derived prostanoid formation to inflammatory pain in mice. Selective deletion of COX‐2 in macrophages (Mac‐COX‐2‐KO) by crossing LysMCre mice with COX‐2flox/flox mice resulted in complete suppression of lipopolysaccharide‐induced prostaglandin (PG) E2, prostacyclin and thromboxane in peritoneal macrophages. Mac‐COX‐2‐KO mice exhibited normal mechanical and heat sensitivity at baseline, as well as normal formalin induced chemical pain, while both mechanical and thermal hyperalgesia were significantly reduced in complete Freund's adjuvant (CFA) evoked hind paw inflammation. Inflammatory cell infiltration and concentrations of PGE2, IL‐1β and TNFα were significantly reduced in Mac‐COX‐2‐KO paw tissues following CFA induction. This was reflected by a reduction in paw swelling. Mechanical and thermal pain hypersensitivity were also reduced in the zymosan‐evoked monoarticular arthritis and collagen II antibody‐induced polyarthritis. We identified PGE2 as the major prostanoid which underlies the effect of macrophage COX‐2 on hyperalgesia using macrophage mPGES‐1 deficient mice obtained by crossing mPGES‐1flox/flox with LysMCre mice (Mac‐mPGES‐1‐KO). These mice fully recapitulated the phenotypes observed with Mac‐COX‐2‐KO. Pretreatment of Mac‐mPGES‐1‐KO mice with celecoxib at a biochemically‐validated COX‐2 selective concentration (100mg/kg/day) failed to reduce CFA‐induced inflammation and hyperalgesia beyond deletion of mPGES‐1 in macrophages, further demonstrating the importance of macrophage‐derived PGE2. This also indicates that central COX‐2 plays only a minor role in this setting. Our results demonstrated that the macrophage COX‐2‐mPGES‐1‐PGE2 biosynthetic pathway might be the dominant source of prostanoids in inflammatory pain hypersensitivity in peripheral tissues and may afford a more targeted approach to NSAID therapy.