Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
J Invest Dermatol. 2014 Nov;134(11):2693-2702. doi: 10.1038/jid.2014.253. Epub 2014 Jun 16.
Skin involvement with dermal fibrosis is a hallmark of systemic sclerosis (SSc), and keratinocytes may be critical regulators of fibroblast function through secretion of chemo-attracting agents, as well as through growth factors and cytokines influencing the phenotype and proliferation rate of fibroblasts. Epithelial-fibroblast interactions have an important role in fibrosis in general. We have characterized the SSc epidermis and asked whether SSc-injured epidermal cells release factors capable of promoting fibrosis. Our results show that the SSc epidermis is hypertrophic, and has altered expression of terminal differentiation markers involucrin, loricrin, and filaggrin. Multiplex profiling revealed that SSc epidermal explants release increased levels of CCN2 and S100A9. CCN2 induction was found to spread into the upper papillary dermis, whereas S100A9 was shown to induce fibroblast proliferation and to enhance fibroblast CCN2 expression via Toll-like receptor 4. These data suggest that the SSc epidermis provides an important source of pro-fibrotic CCN2 and proinflammatory S100A9 in SSc skin, and therefore contributes to the fibrosis and inflammation seen in the disease.
皮肤纤维化是系统性硬化症（SSc）的一个标志，角质形成细胞可能通过分泌趋化因子，以及通过影响成纤维细胞表型和增殖率的生长因子和细胞因子，成为成纤维细胞功能的关键调节者。上皮-成纤维细胞相互作用在纤维化中起着重要作用。我们已经对 SSc 表皮进行了特征描述，并询问 SSc 损伤的表皮细胞是否释放能够促进纤维化的因子。我们的结果表明，SSc 表皮是肥大的，并且终末分化标志物 Involucrin、loricrin 和 filaggrin 的表达发生改变。多重分析显示，SSc 表皮外植体释放的 CCN2 和 S100A9 水平增加。发现 CCN2 的诱导作用会扩散到上部乳突真皮，而 S100A9 则通过 Toll 样受体 4 诱导成纤维细胞增殖，并增强成纤维细胞 CCN2 的表达。这些数据表明，SSc 表皮在 SSc 皮肤中提供了促纤维化的 CCN2 和促炎的 S100A9 的重要来源，因此有助于疾病中所见的纤维化和炎症。
