Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

Abstract

Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor γ (PPAR)γ signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPARγ agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPARγ signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPARγ signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor κB (NFκB) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80(+)iNOS(+) M1 macrophages was decreased whereas numbers of F4/80(+)CD206(+) M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin αX, IL-1β, MIP2α and leptin were decreased at rosiglitazone-treated incisional sites. Moreover, transplantation of rosiglitazone-treated peritoneal macrophages into the incisional sites significantly attenuated hyperalgesia. We speculate that local administration of rosiglitazone significantly alleviated the development of postincisional pain, possibly through regulating macrophage polarity at the inflamed site. PPARγ signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.