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

Andrew P Sawaya,Marjana Tomic-Canic,Rivka C Stone,Spencer Mehdizadeh,Kowser Hasneen,Cheyanne R Head,Katelyn O’Neill,Irena Pastar,Natasa Strbo,Maria I Morasso,Ivan Jozic,Stephen R Brooks

doi:10.1038/s41467-020-18276-0

Andrew P Sawaya, Marjana Tomic-Canic + Show 10 more

Open Access

https://doi.org/10.1038/s41467-020-18276-0

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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.

Highlights

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan
Since the oral mucosa has an intrinsic ability for rapid wound healing, we postulated that this wound-activated gene signature is deregulated in DFUs
We performed a comprehensive comparative analysis between tissue biopsies derived from patients with DFUs and paired human oral mucosa and skin acute wounds using next-generation sequencing and Ingenuity Pathway Analysis (IPA)

Summary

Introduction

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. 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. 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. Diabetic foot ulcers (DFUs), a well-known and devastating complication of Diabetes Mellitus, represent one of the most prevalent types of chronic wounds They are a frequent cause of lower limb amputations with a high mortality rate, overall resulting in ~$9–13 billion in health care costs[1,2]. As the inflammatory response progresses, macrophages transition to an anti-inflammatory and “pro-healing”

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