Chen H, Shi R, Luo B, Yang X, Qiu L, Xiong J, Jiang M, Liu Y, Zhang Z, Wu Y
Department of Basic Medicine, Institute of Immunology, Third Military Medical University of PLA, Chongqing, China.
Cell Death Dis. 2015 Jan 15;6(1):e1597. doi: 10.1038/cddis.2014.544.
Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPARγ) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPARγ expression was upregulated during skin wound healing. Furthermore, macrophage PPARγ deficiency (PPARγ-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 PPARγ-KO mice was significantly increased and local restoration of TNF-α reversed the healing deficit in PPARγ-KO mice. Wound macrophages produced higher levels of TNF-α in PPARγ-KO mice compared with control. In vitro, the higher production of TNF-α by PPARγ-KO macrophages was associated with impaired apoptotic cell clearance. Correspondingly, increased apoptotic cell accumulation was found in skin wound of PPARγ-KO mice. Mechanically, peritoneal and skin wound macrophages expressed lower levels of various phagocytosis-related molecules. In addition, PPARγ agonist accelerated wound healing and reduced local TNF-α expression and wound apoptotic cells accumulation in wild type but not PPARγ-KO mice. Therefore, PPARγ 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.
皮肤伤口巨噬细胞是皮肤修复的关键调节因子，其功能障碍会导致慢性、不愈合的皮肤伤口。过氧化物酶体增殖物激活受体γ（PPARγ）调节巨噬细胞的多种功能，但其在皮肤伤口愈合中的作用尚不清楚。我们观察到，在皮肤伤口愈合过程中，巨噬细胞PPARγ的表达上调。此外，巨噬细胞PPARγ缺陷（PPARγ基因敲除（KO））小鼠的皮肤伤口愈合受损，胶原蛋白沉积、血管生成和肉芽形成减少。PPARγ-KO小鼠伤口中的肿瘤坏死因子α（TNF-α）表达显著增加，局部恢复TNF-α可逆转PPARγ-KO小鼠的愈合缺陷。与对照组相比，PPARγ-KO小鼠伤口中的巨噬细胞产生的TNF-α水平更高。在体外，PPARγ-KO巨噬细胞产生的较高水平的TNF-α与凋亡细胞清除受损有关。相应地，在PPARγ-KO小鼠的皮肤伤口中发现凋亡细胞积累增加。从机制上讲，腹膜和皮肤伤口巨噬细胞表达的各种吞噬相关分子水平较低。此外，PPARγ激动剂可加速野生型小鼠的伤口愈合，降低局部TNF-α表达和伤口凋亡细胞积累，但对PPARγ-KO小鼠无效。因此，PPARγ在控制伤口巨噬细胞清除凋亡细胞以确保有效的皮肤伤口愈合中起关键作用，这为皮肤伤口愈合提供了一个潜在的新治疗靶点。
