Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases
Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases
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靶向 FSTL1 治疗多种纤维化和系统性自身免疫性疾病
DOI：
10.1016/j.ymthe.2020.09.031
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发表时间：
2021-01-06
影响因子：
12.4
通讯作者：
Ning, Wen
中科院分区：
文献类型：
--
作者：
Li, Xiaohe;Fang, Yinshan;Ning, Wen
卵泡抑素样蛋白1(FSTL1)是一种基质细胞蛋白，在发育和疾病过程中表达上调，包括特发性肺纤维化(IPF)、瘢痕疙瘩和关节炎。在过去的几年里，FSTL1的促纤维化和促炎作用得到了广泛的研究，在本报告中也是如此。我们筛选和鉴定了能够阻断FSTL1的表位特异性单抗(NAB)。FSTL1-nabs在体内减轻博莱霉素诱导的肺和真皮纤维化，在体外减轻转化生长因子-β1诱导的人皮肤真皮纤维化。此外，在实验模型中，FSTL1 nabs显著减少了现有的肺纤维化和皮肤纤维化。FSTL1nabs通过降低转化生长因子-β1的反应性、随后的肌成纤维细胞活化和细胞外基质的产生发挥其强大的抗纤维化作用。我们还观察到，FSTL1nabs减轻了胶原诱导的小鼠关节炎的严重程度，并伴随着体外炎症反应的减少。我们的研究结果表明，FSTL1nabs是治疗多器官纤维化和系统性自身免疫性疾病的一种很有前途的新策略。
Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-beta 1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-beta 1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases.