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

H Chen,B Luo,Y Liu,Y Wu,R Shi,L Qiu,Z Zhang,J Xiong,X Yang,M Jiang

doi:10.1038/cddis.2014.544

Abstract

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.

Highlights

The skin is the largest human organ that is essential to protect body against infection and excessive water loss
These results suggest a potential involvement of macrophage PPARγ in the regulation of skin wound healing
As digestion of apoptotic cells by macrophage leading to accumulation of cellular components, such as cholesterol and fatty acids, which may act as endogenous ligands for PPARγ,[41] we incubated both strains of macrophage with ATs, the results showed the mRNA levels of Cd36, Mertk, Mfge[8], Gas[6] and all three C1q subunits were higher in PPARγ-WT macrophages compared with the absence of ATs, which was not observed in PPARγ-knock out (KO) macrophages (Figure 7a)

Summary

Introduction

The skin is the largest human organ that is essential to protect body against infection and excessive water loss. Macrophages are the most important immune cells recruited to the wound sites following skin injury, which exhibit pleiotropic functions to orchestrate the healing process throughout the different phases.[1,7,8] During the earlier inflammation phase, macrophages characterize an proinflammatory phenotype, they release pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α), nitric oxide and IL-6, and produce protease and reactive oxygen species to combat contaminating organisms. Macrophages phagocytose wound debris and apoptotic cells.[9] Phagocytosis of apoptotic cells predominately switches pro-inflammatory macrophages to anti-inflammatory/wound-healing macrophages to resolve wound inflammation and initiate the healing process.[10,11] During the later healing phase, macrophages characterize anti-inflammatory/wound-healing phenotype, they produce many cytokines, chemokines and growth factors to crosstalk with keratinocytes, fibroblasts and endothelial cells, contributing to reepithelialization, collagen deposition, angiogenesis, granulation tissue formation and wound repair.[12] In wound healing, non-functional or dysfunctional macrophages are related with chronic, non-healing wounds.[7,13,14,15] sustaining macrophage normal functions is critical for successful wound healing. PPARα participates in the control of the early inflammation phase of

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Conclusion