Macrophage peroxisome proliferator-activated receptor γ deficiency delays skin wound healing through impairing apoptotic cell clearance in mice

Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPAR gamma expression was upregulated during skin wound healing. Furthermore, macrophage PPAR gamma deficiency (PPAR gamma-knock out (KO)) mice exhibited impaired skin wound healing with reduced collagen deposition, angiogenesis and granulation formation. The tumor necrosis factor alpha (TNF-alpha) expression in wounds of PPAR gamma-KO mice was significantly increased and local restoration of TNF-alpha reversed the healing deficit in PPAR gamma-KO mice. Wound macrophages produced higher levels of TNF-alpha in PPAR gamma-KO mice compared with control. In vitro, the higher production of TNF-alpha by PPAR gamma-KO macrophages was associated with impaired apoptotic cell clearance. Correspondingly, increased apoptotic cell accumulation was found in skin wound of PPAR gamma-KO mice. Mechanically, peritoneal and skin wound macrophages expressed lower levels of various phagocytosis-related molecules. In addition, PPAR gamma agonist accelerated wound healing and reduced local TNF-alpha expression and wound apoptotic cells accumulation in wild type but not PPAR gamma-KO mice. Therefore, PPAR gamma has a pivotal role in controlling wound macrophage clearance of apoptotic cells to ensure efficient skin wound healing, suggesting a potential new therapeutic target for skin wound healing.