Exploring TH17-mediated inflammation in epidermolytic ichthyosis: Clinical and mechanistic insight.

Epidermolytic ichthyosis (EI) is a genetic skin disorder caused by mutations in the KRT1 and KRT10 genes, leading to severe skin abnormalities and inflammation. Current treatment options are limited, emphasizing the need for pathogenesis-based therapies. This study investigates the role of T helper type 17 (TH17) inflammatory responses in EI and explores the mechanisms underlying these responses. We found that patients from the family carrying both KRT1 and MPO mutations exhibited varying degrees of psoriasis-like manifestations and significant therapeutic responses to anti-IL-17 A treatment. The treatment efficacy was also confirmed in patients with KRT10 mutations. Mechanistically, Single-nucleus RNA sequencing revealed significantly elevated levels of TH-17 related cytokines in epidermis and CCR6+ TH17 cell infiltration in the dermis. Additionally, we observed aberrant activation of the IκBα-JNK-c-Jun signaling pathway, leading to heightened IL-8 expression and exacerbated inflammation. Our findings underscore the critical role of TH17-mediated inflammation in the pathogenesis of EI and suggest potential therapeutic avenues targeting this pathway to improve patient outcomes.