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

## TL;DR

People with ISG15 deficiency have trouble healing wounds due to chronic inflammation and fibrosis caused by high levels of interferon.

## Contribution

This study identifies how ISG15 deficiency leads to fibrosis and impaired wound healing through IFN-I-dependent mechanisms.

## Key findings

- ISG15 deficiency causes increased IFN-I–dependent apoptosis and fibrosis in skin and lung tissues.
- ISG15 knockout cells show enhanced epithelial-to-mesenchymal transition and impaired wound healing.
- Macrophage polarization and myofibroblast activation are altered in ISG15-deficient patients.

## Abstract

Human ISG15 deficiency is a monogenic syndrome that poises individuals to a proapoptotic and profibrotic state that can lead to lung and skin damage with scarring and impaired function via chronic inflammation.

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.