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Differential Responses to Folic Acid in Keloid Fibroblasts are Mediated by JAK1/2 and STAT3

24 Pages Posted: 25 Nov 2020 Publication Status: Review Complete

See all articles by Katelyn J. McCann

Katelyn J. McCann

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

Manoj Yadav

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

Ali Alishahedani

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

Alexandra F. Freeman

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

Ian Myles

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

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Abstract

Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism – a form of JAK2/STAT3-driven metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated EMT and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Together, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a previously underappreciated role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.

Suggested Citation

McCann, Katelyn J. and Yadav, Manoj and Alishahedani, Ali and Freeman, Alexandra F. and Myles, Ian, Differential Responses to Folic Acid in Keloid Fibroblasts are Mediated by JAK1/2 and STAT3. Available at SSRN: https://ssrn.com/abstract=3737811 or http://dx.doi.org/10.2139/ssrn.3737811
This version of the paper has not been formally peer reviewed.

Katelyn J. McCann

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology ( email )

Bethesda, MD 20892
United States

Manoj Yadav

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology

Bethesda, MD 20892
United States

Ali Alishahedani

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology ( email )

Bethesda, MD 20892
United States

Alexandra F. Freeman

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology ( email )

Bethesda, MD 20892
United States

Ian Myles (Contact Author)

National Institutes of Health (NIH) - Laboratory of Clinical Immunology and Microbiology ( email )

Bethesda, MD 20892
United States

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