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TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling.

ABSTRACT: 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.

SUBMITTER: Herro R

PROVIDER: S-EPMC7577982 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling.

Herro Rana R Miki Haruka H Sethi Gurupreet S GS Mills David D Mehta Amit Kumar AK Nguyen Xinh-Xinh XX Feghali-Bostwick Carol C Miller Marina M Broide David H DH Soloff Rachel R Croft Michael M

Journal of immunology (Baltimore, Md. : 1950) 20200921 9

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, prim ...[more]

PMID: 32958689

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Project description:PurposeTumor necrosis factor-like ligand 1A (TL1A), especially its secreted form, has been shown to contribute to eosinophilic inflammation and mucus production, cardinal features of asthma, through its receptor, death receptor 3 (DR3). However, the role of the TL1A-DR3 axis in asthma, especially in terms of airway remodeling, has not yet been fully understood.MethodsThe present study investigated the expression and secretion of TL1A in the lung and human bronchial epithelial cells. DR3 small interfering RNA (siRNA), TL1A siRNA, and truncated plasmids were used respectively to identify the function of the TL1A-DR3 axis in vitro. To further validate the roles of the TL1A-DR3 axis in asthma, we collected airway biopsies and sputa from asthmatic patients and constructed a mouse model following rTL1A administration, DR3 knockdown, and TL1A knockout, the asthma-related inflammatory response and the pathological changes in airways were analyzed using various experimental methods. Associated signaling pathways downstream of TL1A knockout in the mouse model were analyzed using RNA sequencing.ResultsTL1A, especially its non-secreted form (nsTL1A) was involved in the remodeling process in asthmatics' airways. Knockdown of TL1A or its receptor DR3 decreased the expression of fibrosis-associated protein in BEAS-2B cells. Reversely, overexpression of nsTL1A in airway epithelial cells facilitated the transforming growth factor-β-induced remodeling progress. In the asthma mouse model, activating the TL1A-DR3 axis contributes to airway inflammation, remodeling, and tissue destruction. Reciprocally, DR3 knockdown or TL1A knockout partly reverses airway remodeling in the asthma model induced by ovalbumin.ConclusionsOur results confirm differential TL1A expression (including its secreted and non-secreted form) in asthma, which modulates remodeling. The shared mechanism of action by which nsTL1A and secreted TL1A exert their effects on asthma development might be mediated via the nuclear factor-κB pathway. The TL1A-DR3 axis presents a promising therapeutic target in asthma.

Dataset Information

TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling.

Publications

TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling.

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