IL-33/ST2 轴通过促进成纤维细胞激活参与系统性硬化症的皮肤纤维化。

IL-33/ST2 axis contributes to the dermal fibrosis of systemic sclerosis via promoting fibroblasts activation.

机构信息

Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Hubei, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.

出版信息

J Dermatol Sci. 2022 Aug;107(2):95-104. doi: 10.1016/j.jdermsci.2022.07.009. Epub 2022 Aug 2.

DOI:10.1016/j.jdermsci.2022.07.009

PMID:35940987

Abstract

BACKGROUND

Systemic sclerosis (SSc) is a chronic immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs. Interleukin-33 (IL-33) has been recently implicated in several autoimmune diseases through its receptor ST2.

OBJECTIVE

The aim of this study was to investigate the role and underlying mechanism of IL-33/ST2 axis in the fibrotic disorder of SSc.

METHODS

The bleomycin (BLM)-induced fibrotic skin and skin biopsies of SSc patients were used to detect the expression of IL-33 and ST2. Human dermal fibroblasts were stimulated with recombinant IL-33(rIL-33) protein and their activation, proliferation and migration were assessed. The role of IL-33/ST2 axis was investigated in mouse fibrosis model via histologically assessing skin fibrosis after IL-33 gene knockout. ST2 neutralizing antibody treatment was also obtained to estimate the possible effect.

RESULTS

The number IL-33 cells and ST2 cells were increased in the lesion skin of SSc patients and BLM-induced mouse. Human skin fibroblasts highly expressed ST2 protein, and the proliferation, migration, and collagen expression were significantly elevated after rIL-33 stimulation, accompanied by the activation of MAPKs and NF-kB pathways. The severity of skin fibrosis was significantly reduced in il33-/- mice compared with WT mice. Blockade of IL-33 receptor using an anti-ST2 neutralizing antibody effectively ameliorated the skin fibrosis.

CONCLUSION

These data indicate that IL-33/ST2 axis contributes to the fibrotic skin injury of SSc via promoting fibroblasts activation, and IL-33/ST2 blockade might serve as a novel strategy to inhibit the fibrosis progression in patients of SSc.

摘要

背景

系统性硬化症（SSc）是一种慢性免疫介导的风湿性疾病，其特征是皮肤和内脏器官纤维化。白细胞介素-33（IL-33）通过其受体 ST2 最近被牵涉到几种自身免疫性疾病中。

目的

本研究旨在探讨 IL-33/ST2 轴在 SSc 纤维化疾病中的作用及其潜在机制。

方法

使用博来霉素（BLM）诱导的纤维化皮肤和 SSc 患者的皮肤活检来检测 IL-33 和 ST2 的表达。用重组 IL-33（rIL-33）蛋白刺激人真皮成纤维细胞，并评估其激活、增殖和迁移。通过 IL-33 基因敲除后评估皮肤纤维化，在小鼠纤维化模型中研究 IL-33/ST2 轴的作用。还进行了 ST2 中和抗体治疗以评估可能的效果。

结果

SSc 患者病变皮肤和 BLM 诱导的小鼠皮肤中 IL-33 细胞和 ST2 细胞数量增加。人皮肤成纤维细胞高度表达 ST2 蛋白，rIL-33 刺激后增殖、迁移和胶原表达显著增加，同时 MAPKs 和 NF-kB 途径被激活。与 WT 小鼠相比，il33-/- 小鼠的皮肤纤维化严重程度明显降低。使用抗 ST2 中和抗体阻断 IL-33 受体可有效改善皮肤纤维化。