Deficiency of vitamin D receptor in keratinocytes augments dermal fibrosis and inflammation in a mouse model of HOCl-induced scleroderma
Deficiency of vitamin D receptor in keratinocytes augments dermal fibrosis and inflammation in a mouse model of HOCl-induced scleroderma
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DOI：
10.1016/j.bbrc.2021.12.085
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发表时间：
2022-01-02
影响因子：
3.1
通讯作者：
Hu, Lizhi
中科院分区：
文献类型：
--
作者：
Ge, Yicheng;Luo, Jing;Hu, Lizhi
硬皮病以广泛的纤维化和血管改变为特征，涉及成纤维细胞过度激活、炎症失控和异常胶原沉积。先前的研究表明，给予1，25(OH)(2)D-3或维生素D类似物可通过调节细胞外基质的动态平衡有效地减少或逆转皮肤纤维化。1，25(OH)(2)D-3的作用是由维生素D受体(VDR)介导的，VDR是一种对皮肤动态平衡至关重要的转录调节因子。尽管有证据表明角质形成细胞-成纤维细胞的相互作用影响硬皮病的发展，但角质形成细胞在硬皮病中的作用仍不清楚。在这里，我们证明了角质形成细胞中VDR的消融极大地加剧了HOCl诱导的小鼠硬皮病的真皮纤维化。与对照组相比，皮肤表皮中VDR的缺乏显著增加了真皮厚度、炎性细胞浸润和严重的胶原沉积。此外，经HOCI治疗后，VDR条件性KO小鼠的胶原过度产生(COL1A1、COL1A2、COL3A1、α-SMA、MMP9、TGF-β1)和促炎细胞因子(IL-1β、IL-6、CXCL1、CXCL2)的mRNA表达水平显著高于对照组。综上所述，这些结果表明角质形成细胞中的VDR在硬皮病的进展中起着关键作用，角质形成细胞和成纤维细胞之间的相互作用值得更多地关注硬皮病的发病机制和治疗。(C)2021 Elsevier Inc.保留所有权利。
Scleroderma, characterized by extensive fibrosis and vascular alterations, involves excessive fibroblast activation, uncontrolled inflammation, and abnormal collagen deposition. Previous studies showed that administrations of either 1,25(OH)(2)D-3 or vitamin D analog effectively decreased or reversed skin fibrosis by regulating the extracellular matrix homeostasis. The actions of 1,25(OH)(2)D-3 are mediated by the vitamin D receptor (VDR), a transcription regulator crucial for skin homeostasis. Although evidence suggests that keratinocyte-fibroblast interaction influences the development of scleroderma, the role of keratinocytes in scleroderma remains unknown. Here, we demonstrated that the ablation of VDR in keratinocytes greatly exacerbated dermal fibrosis in HOCl-induced scleroderma in mice. The deficiency of VDR in the epidermis marked increased dermal thickness, inflammatory cell infiltration, and severe collagen deposition in comparison to the control group in HOCl-treated skin. Moreover, significant elevations in expression levels of mRNA for collagen overproduction (Col1A1, Col1A2, Col3A1, alpha-SMA, MMP9, TGF-beta 1) and proinflammatory cytokines (IL-1 beta, IL-6, CXCL1, CXCL2) were observed in VDR conditional KO versus control mice following HOCI treatment. Collectively, these results suggest that VDR in keratinocytes plays a pivotal role in scleroderma progression, and the interplay between keratinocytes and fibroblasts deserves more attention regarding the exploration of the pathogenesis and treatment for scleroderma. (C) 2021 Elsevier Inc. All rights reserved.