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TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-09-21 , DOI: 10.4049/jimmunol.2000665
Rana Herro 1 , Haruka Miki 1 , Gurupreet S Sethi 1 , David Mills 2 , Amit Kumar Mehta 1 , Xinh-Xinh Nguyen 3 , Carol Feghali-Bostwick 3 , Marina Miller 4 , David H Broide 4 , Rachel Soloff 2 , Michael Croft 4, 5
Affiliation  

Key Points Disrupting TL1A–DR3 interactions abrogates mouse lung fibrosis and airway remodeling. Airway fibroblasts and epithelial cells express DR3 and respond to TL1A. Neutralizing TL1A might be a therapy for airway remodeling in asthma, SSc, and IPF. Lung fibrosis and tissue remodeling are features of chronic diseases such as severe asthma, idiopathic pulmonary fibrosis, and systemic sclerosis. However, fibrosis-targeted therapies are currently limited. We demonstrate in mouse models of allergen- and bleomycin-driven airway inflammation that neutralization of the TNF family cytokine TL1A through Ab blocking or genetic deletion of its receptor DR3 restricted increases in peribronchial smooth muscle mass and accumulation of lung collagen, primary features of remodeling. TL1A was found as a soluble molecule in the airways and expressed on the surface of alveolar macrophages, dendritic cells, innate lymphoid type 2 cells, and subpopulations of lung structural cells. DR3 was found on CD4 T cells, innate lymphoid type 2 cells, macrophages, fibroblasts, and some epithelial cells. Suggesting in part a direct activity on lung structural cells, administration of recombinant TL1A into the naive mouse airways drove remodeling in the absence of other inflammatory stimuli, innate lymphoid cells, and adaptive immunity. Correspondingly, human lung fibroblasts and bronchial epithelial cells were found to express DR3 and responded to TL1A by proliferating and/or producing fibrotic molecules such as collagen and periostin. Reagents that disrupt the interaction of TL1A with DR3 then have the potential to prevent deregulated tissue cell activity in lung diseases that involve fibrosis and remodeling.

中文翻译:

TL1A 促进肺组织纤维化和气道重塑

干扰 TL1A-DR3 相互作用的关键点可消除小鼠肺纤维化和气道重塑。气道成纤维细胞和上皮细胞表达 DR3 并响应 TL1A。中和 TL1A 可能是治疗哮喘、SSc 和 IPF 气道重塑的一种疗法。肺纤维化和组织重塑是严重哮喘、特发性肺纤维化和系统性硬化症等慢性疾病的特征。然而,目前靶向纤维化的疗法是有限的。我们在过敏原和博莱霉素驱动的气道炎症小鼠模型中证明,通过 Ab 阻断或其受体 DR3 的基因缺失来中和 TNF 家族细胞因子 TL1A 限制了支气管周围平滑肌质量和肺胶原蛋白积累的增加,这是重塑的主要特征。TL1A 被发现是气道中的一种可溶性分子,并在肺泡巨噬细胞、树突细胞、2 型先天淋巴样细胞和肺结构细胞亚群的表面表达。在 CD4 T 细胞、先天性淋巴样 2 细胞、巨噬细胞、成纤维细胞和一些上皮细胞上发现了 DR3。在没有其他炎症刺激、先天淋巴细胞和适应性免疫的情况下,将重组 TL1A 施用到幼稚小鼠气道中,这在一定程度上表明对肺结构细胞有直接活性。相应地,发现人肺成纤维细胞和支气管上皮细胞表达 DR3 并通过增殖和/或产生纤维化分子(如胶原蛋白和骨膜蛋白)对 TL1A 做出反应。
更新日期:2020-09-21
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