Ling Shiqi, Xu Beilei, Luo Yang, Fang Xiaokai, Liu Xiaochun, Wang Ao, Zhou Yuan, Zhang Shan, Zong Wenkai, Li Wei, Yao Xu
Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
Department of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
J Invest Dermatol. 2022 Nov;142(11):2968-2977.e10. doi: 10.1016/j.jid.2022.03.035. Epub 2022 May 8.
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.
转谷氨酰胺酶3（TGM3）可预防银屑病中的皮肤炎症，但TGM3在银屑病发病机制中的确切作用和作用机制仍不清楚。在本研究中，我们发现银屑病患者的皮肤病变以及咪喹莫特诱导的银屑病性皮炎小鼠模型中TGM3表达增加。TGM3过表达降低了用银屑病相关细胞因子刺激的原代培养角质形成细胞中促炎因子的产生。TGM3抑制信号转导和转录激活因子3的磷酸化以及TET蛋白3（ten-eleven translocation 3）向p65基因启动子的募集，导致启动子去甲基化减少，随后促炎细胞因子/趋化因子产生受到抑制。TGM3诱导的磷酸化p65抑制也可能降低TET蛋白3的表达。此外，局部应用Tgm3特异性小干扰RNA或泛转谷氨酰胺酶抑制剂半胱胺会加重咪喹莫特诱导的银屑病性皮炎小鼠的皮肤炎症。我们的研究揭示了角质形成细胞中TGM3与TET蛋白3相互作用介导的一种表观遗传途径，用于调节银屑病中的皮肤炎症，为银屑病治疗提供了一个潜在靶点。
