The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis.
The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis.
复制标题
DOI：
10.1038/jid.2015.110
复制
发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
Herro R;Antunes RDS;Aguilera AR;Tamada K;Croft M
包括硬皮病和特应性皮炎在内的几种炎症性疾病表现出真皮增厚、表皮肥大或胶原蛋白过度积累。可能促进这些特征的因素引起了临床治疗的兴趣。我们之前报道过，LIGHT（一种 TNF 超家族分子）可响应过敏原介导肺部胶原蛋白沉积。因此，我们测试了光是否可能同样促进胶原蛋白积累和皮肤纤维化特征。引人注目的是，将重组可溶性光注射到幼鼠体内，无论是皮下还是全身注射，都促进了皮肤中的胶原蛋白沉积，以及真皮和表皮增厚。这复制了博莱霉素的活性，博莱霉素是一种先前用于小鼠硬皮病模型的抗生素。此外，博莱霉素诱导的皮肤纤维化依赖于内源性光活性。 LIGHT 在体内的作用是通过其受体 HVEM 和 LTβR 介导的，并且依赖于先天细胞因子 TSLP 和 TGF-β。此外，我们发现HVEM和LTβR在人表皮角质形成细胞上表达，并且LIGHT可以直接促进这些细胞中TSLP的表达。我们揭示了光对角质细胞的一种未被重视的活性，并表明光可能是硬皮病或特应性皮炎等疾病中皮肤炎症和纤维化的重要介质。
Several inflammatory diseases including scleroderma and atopic dermatitis display dermal thickening, epidermal hypertrophy, or excessive accumulation of collagen. Factors that might promote these features are of interest for clinical therapy. We previously reported that LIGHT, a TNF superfamily molecule, mediated collagen deposition in the lungs in response to allergen. We therefore tested whether LIGHT might similarly promote collagen accumulation and features of skin fibrosis. Strikingly, injection of recombinant soluble LIGHT into naïve mice, either subcutaneously or systemically, promoted collagen deposition in the skin, and dermal and epidermal thickening. This replicated the activity of bleomycin, an antibiotic that has been previously used in models of scleroderma in mice. Moreover skin fibrosis induced by bleomycin was dependent on endogenous LIGHT activity. The action of LIGHT in vivo was mediated via both of its receptors, HVEM and LTβR, and was dependent on the innate cytokine TSLP and TGF-β. Furthermore, we found that HVEM and LTβR were expressed on human epidermal keratinocytes, and that LIGHT could directly promote TSLP expression in these cells. We reveal an unappreciated activity of LIGHT on keratinocytes and suggest that LIGHT may be an important mediator of skin inflammation and fibrosis in diseases such as scleroderma or atopic dermatitis.