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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.

SUBMITTER: Sawaya AP 

PROVIDER: S-EPMC7495445 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Sawaya Andrew P AP   Stone Rivka C RC   Brooks Stephen R SR   Pastar Irena I   Jozic Ivan I   Hasneen Kowser K   O'Neill Katelyn K   Mehdizadeh Spencer S   Head Cheyanne R CR   Strbo Natasa N   Morasso Maria I MI   Tomic-Canic Marjana M  

Nature communications 20200916 1


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 tr  ...[more]

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