Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon–mediated fibrosis

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Abstract
ISG15 deficiency is a type I interferonopathy characterized by elevated circulating type I interferon (IFN-I), intracranial calcifications, fibrotic skin lesions, and occasionally inflammatory lung disease. However, the mechanisms driving immune-mediated fibrosis remain poorly understood. In this study, we combined molecular biology approaches with spatial transcriptomics in ex vivo patient samples and in vitro models to characterize a novel loss-of-function ISG15 variant and to elucidate disease-associated molecular pathways. Analysis of patient skin biopsies revealed increased IFN-I–dependent apoptosis, altered macrophage polarization, enhanced epithelial-to-mesenchymal transition (EMT), and myofibroblast activation. In vitro, ISG15 knockout (KO), but not wild-type (WT), epithelial cells were predisposed to EMT following combined TGF-β and IFN-I stimulation. Additionally, ISG15 KO fibroblasts displayed impaired mechanical wound healing and increased IFN-I–induced apoptosis compared with WT cells. Collectively, our findings suggest that chronic IFN-I exposure in ISG15 deficiency disrupts wound repair, skews macrophage activation, and promotes EMT, contributing to fibrosis across multiple organ systems.
Funding Information
  • National Institutes of Health (R01AI148963)
  • National Institutes of Health (R01AI151029)
  • National Institutes of Health (R01AI127372)
  • National Institutes of Health (R24AI167802)
  • National Institutes of Health (PO1AI186771)

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