Jiang Ziwei, Liu Yuanqi, Li Changwei, Chang Leilei, Wang Wang, Wang Zhenhua, Gao Xiaoguang, Ryffel Bernhard, Wu Yelin, Lai Yuping
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, People's Republic of China.
Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), University Orleans, Orleans, France; University of Cape Town, Institute of Infectious Disease and Molecular Medicine (IDM), Rondebosch, South Africa.
J Invest Dermatol. 2017 Dec;137(12):2620-2629. doi: 10.1016/j.jid.2017.07.820. Epub 2017 Jul 31.
IL-36 family members are highly expressed in hyperproliferative keratinocytes and play an important role in the pathogenesis of skin diseases such as psoriasis. However, whether and how IL-36 cytokines are induced to promote wound healing remains unknown. Here we showed that skin injury increased the expression of IL-36γ to promote wound healing. Mechanistically, the expression of IL-36γ was induced by RNAs from damaged cells via the activation of toll-like receptor 3 (TLR3) and TIR-domain-containing adapter-inducing IFN-β (TRIF) followed by the induction of a zinc finger protein SLUG to abrogate the inhibitory effect of vitamin D receptor (VDR) on the promoter of IL-36γ gene. IL-36γ acted back on keratinocytes to induce REG3A, which regulated keratinocyte proliferation and differentiation, thus promoting wound re-epithelialization. These observations show that skin injury increases IL-36γ via the activation of TLR3-SLUG-VDR axis and that IL-36γ induces REG3A to promote wound healing. These findings also provide insights into pathways contributing to wound repair.
白细胞介素-36（IL-36）家族成员在过度增殖的角质形成细胞中高表达，并在银屑病等皮肤病的发病机制中发挥重要作用。然而，IL-36细胞因子是否以及如何被诱导以促进伤口愈合仍不清楚。在此，我们表明皮肤损伤会增加IL-36γ的表达以促进伤口愈合。机制上，受损细胞的RNA通过激活Toll样受体3（TLR3）和含TIR结构域的接头诱导IFN-β（TRIF）诱导IL-36γ的表达，随后诱导锌指蛋白SLUG以消除维生素D受体（VDR）对IL-36γ基因启动子的抑制作用。IL-36γ作用于角质形成细胞以诱导再生胰岛衍生蛋白3α（REG3A），后者调节角质形成细胞的增殖和分化，从而促进伤口再上皮化。这些观察结果表明，皮肤损伤通过激活TLR3-SLUG-VDR轴增加IL-36γ的表达，并且IL-36γ诱导REG3A以促进伤口愈合。这些发现也为有助于伤口修复的途径提供了见解。
