Myeloid cell mPGES-1 mediates inflammatory pain hypersensitivity in mice

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve inflammatory pain by predominant suppression of cyclooxygenase-2 derived prostaglandin (PG) E2. Innate immune cells contribute to inflammatory pain hypersensitivity and may be an attractive target for novel non-addictive approaches to pain management. We studied the contribution of PGE2 produced by myeloid cell microsomal prostaglandin E synthase -1 (mPGES-1) to peripheral inflammation and hyperalgesia in mice. Selective deletion of mPGES-1 in myeloid cells by crossing LysM-Cre mice with mPGES-1flox/flox mice (Mac-mPGES-1-KO) resulted in significantly reduced mechanical and thermal hyperalgesia in complete Freund's adjuvant (CFA)-evoked hind paw inflammation, zymosan-induced peri-articular inflammation and collagen II antibody-induced arthritis models. Systemic COX-2 inhibition or myeloid cell specific COX-2 deletion (by crossing LysM-Cre with COX-2 flox/flox mice) recapitulated reduction of CFA-induced inflammation and hyperalgesia. In contrast, deletion of mPGES-1 in neurons and glial cells by crossing mPGES-1flox/flox mice with Nestin-Cre mice had no detectable effect on inflammatory pain hypersensitivity. While macrophage recruitment was unaltered, tissue concentrations of PGE2, IL-1β and TNFα were significantly reduced in Mac-mPGES-1-KO paw tissues following CFA induction. Our results demonstrate that myeloid cell mPGES-1 is the dominant source of PGE2 in inflammatory pain hypersensitivity. Targeting myeloid cell mPGES-1 may afford a novel approach to inflammatory pain therapy.

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“…Using digital calipers, we measured basal widths of both hind paws of mice immediately before the onset of inflammation. Peripheral inflammation was induced by injecting 20 μL of complete Freund’s adjuvant (CFA) in the central plantar region of left hind paws (ipsilateral) subcutaneously . At 24 h post-CFA, the paw thickness of the ipsilateral paw, as index of edema, was measured shortly before the start of treatment (0 h time point).…”

“…Peripheral inflammation was induced by injecting 20 μL of complete Freund's adjuvant (CFA) in the central plantar region of left hind paws (ipsilateral) subcutaneously. 34 At 24 h post-CFA, the paw thickness of the ipsilateral paw, as index of edema, was measured shortly before the start of treatment (0 h time point). The paw thickness of the contralateral (uninjured) paw was also measured to assess off-target effects of CFA.…”