The TL1A-DR3 Axis in Asthma: Membrane-Bound and Secreted TL1A Co-Determined the Development of Airway Remodeling

Zhang Jintao; Zhang Dong; Pan Yun; Liu Xiaofei; Xu Jiawei; Qiao Xinrui; Cui Wenjing; Dong Liang

doi:10.4168/aair.2022.14.2.233

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자료유형: 학술저널

저자정보: Zhang Jintao (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Zhang Dong (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Pan Yun (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Liu Xiaofei (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Xu Jiawei (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Qiao Xinrui (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Cui Wenjing (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers) Dong Liang (Department of Respiratory Shandong Qianfoshan Hospital Cheeloo College of Medicine Shandong Univers)

저널정보: 대한천식알레르기학회(구 대한알레르기학회) Allergy, Asthma & Immunology Research Allergy, Asthma & Immunology Research Vol.14 No.2

발행연도: 2022.3

수록면: 233 - 253 (21page)

DOI: 10.4168/aair.2022.14.2.233

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Purpose: Tumor 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. Methods: The 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. Results: TL1A, 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. Conclusions: Our 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.

#Asthma #airway remodeling #airway inflammation #tumor necrosis factor #TL1A #therapeutic target

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