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

•Macrophages are one of the main cellular targets for PPAR-γ activation when peripherally administered.•Anti-inflammatory features of PPAR-γ activation by 15d-PGJ2 are related to M2-like polarization.•HO-1 is crucial for macrophage polarization and for preventing recruitment of animal and human neutrophils.•Ca2+/calmodulin (CaMKII) is not involved in the antinociceptive actions of peripheral PPAR-γ in TMJ. Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ 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-γ 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-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ2 induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca2+/calmodulin expression did not change after PPAR-γ 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-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.