Macrophage PPARγ and impaired wound healing in type 2 diabetes

Abstract

Macrophages undergo a transition from pro-inflammatory to healing-associated phenotypes that is critical for efficient wound healing. However, the regulation of this transition during normal and impaired healing remains to be elucidated. In our studies, the switch in macrophage phenotypes during skin wound healing was associated with upregulation of the peroxisome proliferator-activated receptor (PPAR)-γ and its downstream targets, along with increased mitochondrial content. In the setting of diabetes, upregulation of PPAR-γ activity was impaired by sustained expression of IL-1β in both mouse and human wounds. In addition, experiments with myeloid-specific PPAR-γ knockout mice indicated that loss of PPAR-γ in macrophages is sufficient to prolong wound inflammation and delay healing. Furthermore, PPAR-γ agonists promoted a healing-associated macrophage phenotype both in vitro and in vivo, even in the diabetic wound environment. Importantly, topical administration of PPAR-γ agonists improved healing in diabetic mice, suggesting an appealing strategy for downregulating inflammation and improving healing of chronic wounds.

Skin Wound Healing: An Update on the Current Knowledge and Concepts

“…This supports the current paradigm of the M1-M2 switch [1,15]. If the M1-M2 transition does not occur, nonhealing or chronic wounds such as venous ulcers and diabetic wounds are the result [16,17,18]. These observations underpin the intimate and important role of macrophages throughout the process of skin wound healing.…”

Diabetes medications: Impact on inflammation and wound healing

“…Since IL-1β is predominantly produced by monocytes and macrophages (Mirza, Fang et al 2015), use of an inflammasome inhibitor to lower IL-1β expression may be an appealing anti-inflammatory strategy since these inflammatory cells are key regulators of the wound healing process (Koh and DiPietro 2011). Notably, treatment of excisional wounds on db/db diabetic mice with topical glyburide was shown to accelerate epithelialization and increase granulation tissue formation.…”

“…Recent studies have reported that topical treatment of wounds on db/db diabetic mice with rosiglitazone reported improved wound healing by inducing a switch of pro-inflammatory macrophages towards a pro-healing phenotype (Mirza, Fang et al 2015). They also found that diabetic wounds from mouse and human patients showed impaired PPAR-γ activity due to sustained expression of IL-1β, which maintained wounds in a persistent inflammatory state.…”

“…However, prolonged inflammatory responses in wounds are associated with impaired healing (Loots, Lamme et al 1998, Eming, Martin et al 2014). Our laboratory has demonstrated that macrophages exhibit a persistent pro-inflammatory phenotype expressing high levels of pro-inflammatory molecules like interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and the protease matrix metalloprotease-9 (MMP-9) during impaired healing associated with diabetes (Mirza, Fang et al 2013, Mirza, Fang et al 2014, Mirza, Fang et al 2015). This pro-inflammatory phenotype may be induced by hyperglycemia, which has been reported to increase oxidative and inflammatory stress via production of reactive oxygen species (ROS) and TNF-α (Mohanty, Hamouda et al 2000, Aljada, Friedman et al 2006).…”

“…Since macrophages are the primary producers of pro-inflammatory cytokines in wounds (Mirza, Fang et al 2015), recent wound healing studies have focused on studying macrophage dysfunction in chronic wounds of diabetic humans and mice. Classically activated or M1-like macrophages are known for killing microorganisms and producing pro-inflammatory cytokines, such as IL-1β, TNF-α and interleukin 6 (IL-6) (Novak and Koh 2013).…”