Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

Abstract

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of “ideal” adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.

Glucose inhibits haemostasis and accelerates diet-induced hyperlipidaemia in zebrafish larvae

“…Our finding that high glucose environments reduce the recruitment of neutrophils to a tail wound is consistent with studies of diabetic foot ulcers [2, 4]. In mammals, high glucose environments have been shown to interfere with metabolites and enzymes related to neutrophil function [37].…”

“…Altered innate immune cell recruitment to wounds is a conserved feature of hyperglycaemia in mammals [4, 5, 29–31]. To determine if this phenomenon was conserved in zebrafish embryos, we utilised the tail transection wound model which causes reproducible leukocyte recruitment [23] (Figure 2A).…”

“…Hyperglycaemic damage to the microvasculature is hypothesised to underpin much of the pathology associated with diabetes in mammals, including perturbations to leukocyte biology, haemostasis, and the accumulation of lipid laden macrophages in the vessel wall [1–4]. Previous mammalian research has demonstrated that hyperglycaemia damages the microvasculature resulting in reduced expression of endothelial adhesion molecules for immune cell recruitment [2, 4]. As a result, fewer neutrophils and macrophages are recruited to diabetic wounds [1, 2, 5].…”

Gut–Skin Axis: Current Knowledge of the Interrelationship between Microbial Dysbiosis and Skin Conditions

“…The prevalence of chronic wounds is higher in older people with underlying pathologies including diabetes mellitus, vascular disease, and obesity [311]. The cellular programs restoring the skin barrier do not function properly in chronic wounds [308,312,313]. Impaired wound healing is characterized by accelerated keratinocyte proliferation, impaired migration, and fibrosis.…”

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

“…These hard-to-treat wounds pose a significant medical challenge; as their prevalence has steadily increased over time and only modest therapeutic advancements have come from animal studies [ 30 , 31 ]. While tremendous efforts have uncovered defects in cellular composition and function during the proliferative phase of repair, animal models have recently revealed that reduced activation of early inflammatory responses is associated with delayed healing [ 32 , 33 , 34 ]. Due to their role in ECM production, dermal mesenchymal cells have been studied in the context of ECM formation and maturation; however, emerging evidence has revealed that adipocytes and fibroblasts can also promote inflammation.…”