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

Andrew P. Sawaya, Rivka C. Stone, Stephen R. Brooks, Irena Pastar, Ivan Jozic, Kowser Hasneen, Katelyn O’Neill, Spencer Mehdizadeh, Cheyanne R. Head, Natasa Strbo, Maria I. Morasso () and Marjana Tomic-Canic ()
Additional contact information
Andrew P. Sawaya: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Rivka C. Stone: University of Miami Miller School of Medicine
Stephen R. Brooks: Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Irena Pastar: University of Miami Miller School of Medicine
Ivan Jozic: University of Miami Miller School of Medicine
Kowser Hasneen: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Katelyn O’Neill: University of Miami Miller School of Medicine
Spencer Mehdizadeh: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Cheyanne R. Head: University of Miami Miller School of Medicine
Natasa Strbo: University of Miami Miller School of Medicine
Maria I. Morasso: Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Marjana Tomic-Canic: University of Miami Miller School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18276-0

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