Activation of PPAR-γ induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1

Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-gamma) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-gamma activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-gamma activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-gamma activation. Our results demonstrate that PPAR-gamma activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ(2) induces the PPAR-gamma heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-gamma activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca2+/calmodulin expression did not change after PPAR-gamma activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K+ATP channel pathway. In summary, the anti-inflammatory actions induced by PPAR-gamma activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.