TCN2 drives psoriasis-like inflammation and keratinocyte hyperproliferation by activating IL-1β and STAT3 pathways

Psoriasis is a chronic immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation, immune cell infiltration, and persistent inflammatory signaling. Current standard-of-care treatments often target broad immune pathways, but specific drivers of keratinocyte dysfunction remain underexplored. While transcobalamin 2 (TCN2), a vitamin B12-binding protein, has been linked to other autoimmune diseases, its precise role in psoriatic pathogenesis and its interaction with key inflammatory pathways like STAT3 has been unclear, representing a critical knowledge gap.

Researchers investigated TCN2's role in psoriasis using human samples, a mouse model, and cell lines. They analyzed TCN2 expression in lesional skin and peripheral blood mononuclear cells (PBMCs) from psoriasis patients before and after biologic therapy. An imiquimod (IMQ)-induced psoriasis model was established in wild-type and Tcn2-deficient (Tcn2-/-) mice to assess disease severity. Additionally, TCN2-knockdown HaCaT cells were used to study keratinocyte proliferation and inflammatory factor expression. Primary endpoints included TCN2 levels, skin lesion attenuation, epidermal hyperplasia, inflammation, and transcriptomic analysis via qPCR and RNA-seq.

TCN2 expression was significantly elevated in both lesional skin and PBMCs from psoriasis patients, and these levels declined following biologic therapy. Similarly, increased TCN2 expression was observed in imiquimod (IMQ)-induced psoriatic lesions in mice. Compared with wild-type controls, Tcn2-/- mice developed attenuated skin lesions, exhibiting reduced epidermal hyperplasia and inflammation. Transcriptomic analysis of lesional skin from Tcn2-/- mice revealed a downregulation of inflammatory mediators, including S100A7, S100A8, S100A9, IL-1β, and IL-6.

Crucially, Tcn2-/- mice also showed significant suppression of STAT3 signaling, a key pathway in psoriasis. In parallel, TCN2-knockdown HaCaT cells exhibited impaired proliferation due to G1-phase arrest, along with reduced expression of proinflammatory factors, confirming TCN2's direct role in keratinocyte biology.