Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital Campus, University College London Medical School, London, UK.
MuriGenics, Inc, Vallejo, CA, USA.
Rheumatology (Oxford). 2020 Sep 1;59(9):2625-2636. doi: 10.1093/rheumatology/keaa195.
Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis.
IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma.
IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA.
IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients.
浸润 T 细胞释放的细胞因子可能促进硬皮病纤维化的发生机制。本研究旨在探讨 Th2 细胞因子 IL-31 及其受体 IL-31RA 在硬皮病皮肤和肺纤维化中的作用。
通过 ELISA 法检测硬皮病患者血浆中 IL-31 的含量，通过免疫组织化学法检测纤维化皮肤和肺组织中 IL-31 的含量。通过 qPCR 法检测组织固有细胞中 IL-31RA 的含量。采用下一代测序技术对正常皮肤成纤维细胞对 IL-31 的反应进行分析。在野生型 Balb/c 小鼠中，通过皮下微型泵给予 IL-31，或联合给予 TGFβ，并通过组织学和血浆 ELISA 检测纤维化反应。
在一部分硬皮病患者的血浆和纤维化皮肤及肺组织中，IL-31 水平较高，下游与疾病过程相关的细胞（包括皮肤和肺成纤维细胞）通过 miR326 的表观遗传调控丧失而过度表达受体。在皮肤成纤维细胞中，IL-31 诱导与细胞生长和增殖、无氧代谢和矿化相关的下一代测序谱，与血管生成和血管修复呈负相关，并通过 pSTAT3 促进表型变化，包括迁移和胶原蛋白释放，类似于疾病中的激活状态。在小鼠中，IL-31 诱导皮肤和肺纤维化。与 TGFβ 无协同作用，TGFβ 抑制 IL-31RA。
IL-31/IL-31RA 被确认为候选促纤维化途径，可能在一部分硬皮病患者中导致皮肤和肺纤维化。
