Macrophage peroxisome proliferator-activated receptor γ 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 (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.

Diabetes medications: Impact on inflammation and wound healing

“…An additional 20 patients taking 4mg rosiglitazone showed similar but less robust effects than patients on pioglitazone except for no changes in TNF-α or lipid profile. Overall, a recent meta-analysis of 27 randomized controlled trials evaluating pioglitazone and rosiglitazone therapy on circulating levels of inflammatory markers in patients with type 2 diabetes showed that both medications decreased levels of hs-CRP and MCP-1 with limited effects on IL-6 and MMP-9 (Chen, Yan et al 2015). …”

“…Mechanistically, PPAR-γ has been reported to control the inflammatory response by inhibition AP-1, NF-κβ, or STAT-3 signaling pathways in macrophages (Chinetti, Fruchart et al 2003) and likely other cells. Additionally, a recent study showed that macrophages deficient in PPARγ from PPARγ knock out mice exhibited impaired skin wound healing with high expression of TNF-α and reduced collagen deposition, angiogenesis and granulation formation (Chen, Shi et al 2015). They also found that treatment with rosiglitazone on wounds of wild type mice resulted in accelerated wound healing and decreased TNF-α levels compared to wounds of vehicle treated controls, but that rosiglitazone did not elicit these changes in PPARγ-knock out mice.…”

Transcriptional control of microglia phenotypes in health and disease

“…In adiposeresident macrophages, members of the PPAR family are implicated in suppressing fatty acid-induced inflammation associated with obesity and metabolic syndrome by increasing fatty acid oxidation (109). PPARγ is a central switch that inhibits the expression of proinflammatory mediators (110) and induces a wound healing phenotype (111,112). However, the role of PPARs in microglia and neuroinflammation is still poorly understood.…”

Myeloid Cells in Cutaneous Wound Repair

“…Indeed, injection of HMGB1 into E15 wounds, which normally heal scarlessly, results in scar formation associated with Mϕ recruitment and increased wound fibroblasts (118). Recently, Chen et al demonstrated that Mϕ-specific deficiency of peroxisome proliferatoractivated receptor γ results in elevated TNF-α levels, leading to impaired apoptotic cell clearance, which in turn resulted in poor wound repair with reduced collagen deposition and angiogenesis (35).…”

“…The most fully characterized model organism is the mouse (Mus musculus), in which transgenic and knockout studies have helped refine our understanding of the function of each of these lineages in the repair process (6,35,36). Intravital microscopy enables live imaging of immune cell recruitment to mouse wounds, but the translucent zebrafish (Danio rerio) also offers opportunities here with ease of in vivo imaging and genetic advantages over the mouse.…”