TCN2 promotes psoriatic skin inflammation and keratinocyte proliferation via the IL-1beta-STAT3 pathway
Psoriasis, a chronic immune-mediated inflammatory skin disorder, exerts systemic impacts across multiple organs. Although transcobalamin 2 (TCN2) has been reported to be associated with several autoimmune diseases, its role in psoriasis remains elusive. Hence, we investigated the role of TCN2 in psoriasis pathogenesis. Our results indicated that TCN2 was highly expressed in the skin tissues and peripheral blood mononuclear cells (PBMCs) of psoriatic patients, with downregulation following biologic therapy. Moreover, imiquimod (IMQ) - induced psoriasis in mice exhibited heightened TCN2 expression. To further explore the role of TCN2 in psoriasis, we generated Tcn2-deficient (Tcn2-/-) mice and established a psoriasis model using IMQ. IMQ-treated Tcn2-/- mice displayed milder psoriatic lesions and a lower level of inflammation. RNA-seq analysis of lesional skin revealed significant downregulation of inflammatory mediators (S100A7, S100A8, S100A9, IL-1beta, IL-6) and suppression of STAT3 signaling in Tcn2-/- mice compared to WT-IMQ mice. Parallel in vitro experiments using TCN2-knockout HaCaT cells demonstrated cell cycle arrest. Collectively, our findings highlight TCN2 as a critical regulator of psoriatic inflammation, proposing it as a novel therapeutic target.