Transglutaminase 3 Attenuates Skin Inflammation in Psoriasis by Inhibiting NF-κB Activation through Phosphorylated STAT3–TET3 Signaling

Abstract

Transglutaminase 3 (TGM3) protects against skin inflammation in psoriasis, but the precise role and mechanism of action of TGM3 in the pathogenesis of psoriasis remain unclear. In this study, we show that TGM3 expression was increased in the skin lesions of patients with psoriasis and a mouse model of imiquimod-induced psoriatic dermatitis. TGM3 overexpression decreased the production of proinflammatory factors in cultured primary keratinocytes stimulated with psoriasis-related cytokines. TGM3 inhibited the phosphorylation of signal transducer and activator of transcription 3 and the recruitment of ten-eleven translocation 3 to the p65 gene promoter, resulting in decreased promoter demethylation and subsequent suppression of proinflammatory cytokine/chemokine production. TGM3-induced inhibition of phosphorylated p65 might also decrease ten-eleven translocation 3 expression. Moreover, topical application of Tgm3-specific small interfering RNA or the pan-transglutaminase inhibitor cysteamine exacerbated skin inflammation in mice with imiquimod-induced psoriatic dermatitis. Our study revealed an epigenetic pathway mediated by the interaction between TGM3 and ten-eleven translocation 3 in keratinocytes for regulation of skin inflammation in psoriasis, providing a potential target for psoriasis treatment.