Enhanced uric acid degradation attenuates psoriasiform dermatitis via the mtROS–CCL20–CCR6–IL-17 axis

Abstract

Psoriasis is an interleukin (IL)-23–IL-17–driven chronic inflammatory skin disease characterized by epidermal hyperproliferation. Although psoriasis is frequently associated with hyperuricemia—generally considered a consequence of enhanced local purine metabolism—the direct contribution of uric acid (UA) to psoriatic skin inflammation remains unclear. Here, we investigated whether promoting UA degradation modulates psoriasiform dermatitis using an imiquimod (IMQ)-induced mouse model of psoriasis. IMQ-induced dermatitis was established in wild-type (WT) mice and uricase-overexpressing transgenic mice (UOXTg) with enhanced UA degradation. IMQ application markedly increased UA levels in lesional skin of WT mice, whereas this increase was significantly suppressed in UOXTg mice. Compared with WT controls, UOXTg mice exhibited attenuated psoriasiform dermatitis, as evidenced by reduced clinical severity scores, decreased epidermal thickness, and lower expression of IL-17A and C-C motif chemokine ligand 20 (CCL20) in lesional skin. Consistent with reduced CCL20 expression, infiltration of CC chemokine receptor 6 (CCR6)–positive IL-17A–producing γδ T cells into skin lesions was significantly diminished in UOXTg mice, whereas their frequencies in skin-draining lymph nodes and spleen remained unchanged. In keratinocytes, UA enhanced IMQ-induced CCL20 expression and promoted mitochondrial Ca²⁺ accumulation and mitochondrial reactive oxygen species (mtROS) production. Pharmacological inhibition of mtROS using mitoquinone (MitoQ) suppressed UA-dependent CCL20 upregulation. Moreover, lesional skin of UOXTg mice exhibited reduced mitochondrial oxidative stress, and MitoQ administration diminished the difference in disease severity between WT and UOXTg mice. Collectively, these findings demonstrate that enhanced UA degradation attenuates psoriasiform dermatitis by limiting mtROS-dependent CCL20 induction and subsequent recruitment of pathogenic IL-17A–producing γδ T cells. These results identify local UA metabolism and mitochondrial oxidative stress as potential therapeutic targets in psoriasis.