Xie Lihu, Long Xiaoping, Mo Meili, Jiang Jinmei, Zhang Qingxiu, Long Mei, Li Mei
Department of Rheumatology and Immunology, The First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, PR China.
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, PR China.
Mol Immunol. 2023 May;157:146-157. doi: 10.1016/j.molimm.2023.03.017. Epub 2023 Apr 5.
Interleukin (IL)- 33 is a tissue-derive proinflammatory cytokine that promotes fibrosis in systemic sclerosis (SSc). microRNA (miR)- 214 expression has been elaborated to be downregulated in SSc patients and exert anti-fibrotic and anti-inflammatory effects. This study elucidates the role of bone marrow mesenchymal stem cell-derived exosome (BMSC-Exos)-delivered miR-214 in SSc and the relationship between this miR and IL-33/ST2 axis. SSc clinical samples were obtained to evaluate levels of miR-214, IL-33, and ST2. Primary fibroblasts and BMSC-Exos were extracted, followed by the co-culture of PKH6-labeled BMSC-Exos and fibroblasts. Subsequently, Exos extracted from miR-214 inhibitor-transfected BMSCs were co-cultured with TGF-β1-stimulated fibroblasts, after which the expression of fibrotic markers, miR-214, IL-33, and ST2, as well as fibroblast proliferation and migration, was determined. A skin fibrosis mouse model was induced with bleomycin (BLM) and treated with BMSC-Exos. Collagen fiber accumulation, collagen content, α-SMA expression, and IL-33 and ST2 levels were examined in BLM-treated or IL-33-knockout mice. IL-33 and ST2 were upregulated and miR-214 was downregulated in SSc patients. Mechanistically, miR-214 targeted IL-33 and blocked the IL-33/ST2 axis. BMSC-Exos delivering miR-214 inhibitor augmented proliferation, migration, and fibrotic gene expression in TGF-β1-stimulated fibroblasts. Similarly, IL-33 induced migration, proliferation, and fibrotic gene expression in fibroblasts via ST2. In BLM-treated mice, IL-33 knockout suppressed skin fibrosis, and BMSC-Exos delivered miR-214 to suppress the IL-33/ST2 axis, thus mitigating skin fibrosis. Conclusively, BMSC-Exos alleviate skin fibrosis through the blockade of the IL-33/ST2 axis by delivering miR-214.
白细胞介素（IL）-33是一种组织来源的促炎细胞因子，可促进系统性硬化症（SSc）中的纤维化。微小RNA（miR）-214的表达在SSc患者中已被证实下调，并具有抗纤维化和抗炎作用。本研究阐明了骨髓间充质干细胞来源的外泌体（BMSC-Exos）递送的miR-214在SSc中的作用以及该miR与IL-33/ST2轴之间的关系。获取SSc临床样本以评估miR-214、IL-33和ST2的水平。提取原代成纤维细胞和BMSC-Exos，随后将PKH6标记的BMSC-Exos与成纤维细胞共培养。随后，将从转染了miR-214抑制剂的BMSC中提取的外泌体与转化生长因子-β1（TGF-β1）刺激的成纤维细胞共培养，之后测定纤维化标志物、miR-214、IL-33和ST2的表达以及成纤维细胞的增殖和迁移。用博来霉素（BLM）诱导建立皮肤纤维化小鼠模型并用BMSC-Exos进行治疗。在BLM处理的或IL-33基因敲除的小鼠中检测胶原纤维积累、胶原含量、α-平滑肌肌动蛋白（α-SMA）表达以及IL-33和ST2水平。在SSc患者中，IL-33和ST2上调而miR-214下调。机制上，miR-214靶向IL-33并阻断IL-33/ST2轴。递送miR-214抑制剂的BMSC-Exos增强了TGF-β1刺激的成纤维细胞的增殖、迁移和纤维化基因表达。同样，IL-33通过ST2诱导成纤维细胞的迁移、增殖和纤维化基因表达。在BLM处理的小鼠中，IL-33基因敲除抑制了皮肤纤维化，而BMSC-Exos递送miR-214以抑制IL-33/ST2轴，从而减轻皮肤纤维化。总之，BMSC-Exos通过递送miR-214阻断IL-33/ST2轴来减轻皮肤纤维化。
