RT Journal Article
SR Electronic
T1 TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP ji2000665
DO 10.4049/jimmunol.2000665
A1 Herro, Rana
A1 Miki, Haruka
A1 Sethi, Gurupreet S.
A1 Mills, David
A1 Mehta, Amit Kumar
A1 Nguyen, Xinh-Xinh
A1 Feghali-Bostwick, Carol
A1 Miller, Marina
A1 Broide, David H.
A1 Soloff, Rachel
A1 Croft, Michael
YR 2020
UL http://www.jimmunol.org/content/early/2020/09/19/jimmunol.2000665.abstract
AB 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.