The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib

W Wang, S Bhattacharyya… - … of Scleroderma and …, 2020 - journals.sagepub.com
W Wang, S Bhattacharyya, RG Marangoni, M Carns, K Dennis-Aren, A Yeldandi, J Wei
Journal of Scleroderma and Related Disorders, 2020journals.sagepub.com
Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis;
accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast
activation underlies organ fibrosis, but the key extracellular cues driving persistence of the
process remain incompletely characterized. Objectives: The objectives were to evaluate
activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from
systemic sclerosis patients and effects of the Food and Drug Administration–approved …
Rationale
Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized.
Objectives
The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models.
Methods
Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice.
Conclusion
These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.
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