Transforming growth factor‐ β 1 mediates psoriasis‐like lesions via a Smad3‐dependent mechanism in mice

Summary Transforming growth factor ( TGF )‐ β 1 signals through downstream Smad‐dependent and ‐independent pathways to exert its biological actions. It has been reported that overexpression of TGF ‐ β 1 results in the development of psoriasis‐like lesions in a mouse model of K5. TGF ‐ β WT transgenic mice. However, the signalling mechanisms by which TGF ‐ β 1 mediates the development of psoriasis‐like lesions remain unknown. The aim of the present study was to investigate the hypothesis that TGF ‐ β 1 mediates the development of psoriasis‐like lesions via a Smad3‐dependent mechanism. This was tested in a mouse model of K5. TGF ‐ β WT transgenic mice by blocking TGF ‐ β signalling with a specific Smad3 inhibitor. Topical treatment with a Smad3 inhibitor markedly blocked TGF ‐ β /Smad3 signalling and progressive psoriasis‐like lesions in K5. TGF ‐ β WT transgenic mice, as evidenced by decreased skin severity scores, double skin fold thickness ( DSFT ) scores, infiltration of CD 3 + T cells and F4/80 + macrophages and the degree of fibrosis in the dermis. This was associated with a marked reduction in TGF ‐ β 1, interleukin ( IL )‐6, IL ‐23 and IL ‐17A both locally in skin plaque lesions and systemically in the plasma, resulting in inhibition of both the T helper (Th) 17 cell transcription factor ROR γ t and accumulation of CD 4 + IL ‐17A + cells within the skin plaque lesions. In conclusion, TGF ‐ β 1 mediates the development of psoriasis‐like lesions via a Smad3‐dependent, Th17‐mediated mechanism. Targeting TGF ‐ β /Smad3 signalling with a Smad3 inhibitor may represent a novel and effective therapy for psoriasis.