CaMK4 drives pathogenic Th17 cell response via the STAT3/RORγt axis in psoriasis

Abstract

Abstract Psoriasis is a chronic inflammatory skin disease driven by dysregulated immune responses, particularly those mediated by pathogenic Th17 cell response; however, the key intracellular signaling molecules that specifically regulate Th17 cell pathogenicity in the skin remain incompletely defined. Here, we showed that CaMK4 was highly expressed in CD4 + T cells from psoriatic lesional skin in both humans and mice. T cell-specific Camk4 deletion alleviated imiquimod (IMQ)-induced psoriasiform dermatitis, accompanied by reduced epidermal hyperplasia and decreased frequencies of skin RORγt⁺ and IL-17A⁺ CD4⁺ T cells. Mechanistically, CaMK4 mediated IL-23-triggered phosphorylation of STAT3, which promoted the expression of RORγt and IL-17A in CD4⁺ T cells. In vivo, reconstitution of STAT3 activity restored psoriasiform dermatitis in T cell-specific Camk4 -deficient mice. Furthermore, topical application of a CaMK4 inhibitor ameliorated IMQ-induced skin pathology. Clinically, CAMK4 expression positively correlated with RORC and IL17A levels in CD4⁺ T cells from psoriasis patients, and inhibition of CaMK4 suppressed IL-23-induced Th17 cell response both in patient-derived CD4⁺ T cells and in ex vivo human skin explants. These findings identify CaMK4 as a critical driver of pathogenic Th17 cell response via the STAT3/RORγt axis in psoriasis and suggest that it may represent a potential target for further therapeutic exploration.