Immunological liver-skin axis: a systemic Vγ4+ γδT17 cell responselinks psoriasis-like inflammation and MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and psoriasis frequently co-occur and share interleukin-17 (IL-17)-mediated inflammatory mechanisms. Using a murine model combining Western-diet-induced early MASLD with chronic imiquimod-triggered psoriasis-like dermatitis, we observed exacerbated skin inflammation with increased cellularity and systemic IL-17-driven immune activation. In mice with psoriasis-like skin inflammation, hepatic {gamma}{delta}T cells shifted from IFN-{gamma}-producing {gamma}{delta}T1 toward IL-17-secreting {gamma}{delta}T17 cells, accompanied by an acute-phase response and induction of hepatic lipogenic gene expression. Single-cell RNA sequencing revealed an expansion of V{gamma}4 {gamma}{delta}T17 cells engaged in IL-17 and TGF-{beta} signaling, consistent with early fibrogenic responses. Together, these findings identify V{gamma}4 {gamma}{delta}T17 cells as a mechanistic link between psoriasis and MASLD, promoting systemic inflammation and early hepatic remodeling. Consistently, in a clinical cohort of patients with moderate-to-severe psoriasis and co-morbid MASLD, IL-17-targeted therapy improved hepatic steatosis, underscoring the translational relevance of this immunological axis.