Exploring T_H17-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 (T_H17) 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 T_H-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 T_H17-mediated inflammation in the pathogenesis of EI and suggest potential therapeutic avenues targeting this pathway to improve patient outcomes.