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

Abstract

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