Abstract
SUMMARYAcute inflammation in response to injury is a tightly regulated process by which subsets of leukocytes are recruited to the injured tissue and undergo behavioural changes that are essential for effective tissue repair and regeneration. The diabetic wound environment is characterised by excessive and prolonged inflammation that is linked to poor progression of healing and, in humans, the development of diabetic foot ulcers. However, the underlying mechanisms contributing to excessive inflammation remain poorly understood. Here we show in a murine model that the diabetic environment induces stable intrinsic changes in haematopoietic cells. These changes lead to a hyper-responsive phenotype to both pro-inflammatory and anti-inflammatory stimuli, producing extreme M1 and M2 polarised cells. During early wound healing, myeloid cells in diabetic mice show hyperpolarisation towards both M1 and M2 phenotypes, whereas, at late stages of healing, when non-diabetic macrophages have transitioned to an M2 phenotype, diabetic wound macrophages continue to display an M1 phenotype. Intriguingly, we show that this population predominantly consists of Gr-1+ CD11b+ CD14+ cells that have been previously reported as ‘inflammatory macrophages’ recruited to injured tissue in the early stages of wound healing. Finally, we show that this phenomenon is directly relevant to human diabetic ulcers, for which M2 polarisation predicts healing outcome. Thus, treatments focused at targeting this inflammatory cell subset could prove beneficial for pathological tissue repair.
Highlights
The inflammatory response to injury is an ancient and evolutionarily conserved process that involves recruitment of circulating cells to damaged tissue to neutralise invading pathogens and remove local debris
The authors used a well-characterised mouse model of type 2 diabetes to determine how the diabetic environment affects the differential activation of myeloid progenitors. They demonstrate that diabetes induces stable cell-intrinsic changes that pre-prime myeloid cells to hyperpolarise towards ‘M1’ pro-inflammatory macrophages and ‘M2’ antiinflammatory macrophages during the early stages of wound healing
During the late stages of wound healing, extrinsic factors inhibit the development of M2 antiinflammatory macrophages; the pro-inflammatory response mediated by M1 macrophages is prolonged
Summary
The inflammatory response to injury is an ancient and evolutionarily conserved process that involves recruitment of circulating cells to damaged tissue to neutralise invading pathogens and remove local debris. Some studies have suggested that inflammation might impair the tissue repair process (Cooper et al, 2004; Dovi et al, 2003), whereas more recent conditional macrophage depletion studies have demonstrated their essential and positive contribution to adult cutaneous repair (Lucas et al, 2010; Mirza et al, 2009). It remains unclear whether these positive inflammatory cell roles translate into pathological wound healing environments, such as in diabetes. This dysfunctional phenotype might be due to abnormalities in myeloid
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