Abstract
Mucus secretion is an important feature of asthma that highly correlates with morbidity. Current therapies, including administration of mucolytics and anti-inflammatory drugs, show limited effectiveness and durability, underscoring the need for novel effective and longer lasting therapeutic approaches. Here we show that mucus production in the lungs is regulated by the TNF superfamily member 15 (TL1A) acting through the mucus–inducing cytokine IL-13. TL1A induces IL13 expression by innate lymphoid cells leading to mucus production, in addition to promoting airway inflammation and fibrosis. Reciprocally, neutralization of IL13 signaling through its receptor (IL4Rα), completely reverses TL1A-induced mucus secretion, while maintaining airway inflammation and fibrosis. Importance of TL1A is further demonstrated using a preclinical asthma model induced by chronic house dust mite exposure where TL1A neutralization by genetic deletion or antagonistic blockade of its receptor DR3 protected against mucus production and fibrosis. Thus, TL1A presents a promising therapeutic target that out benefits IL13 in reversing mucus production, airway inflammation and fibrosis, cardinal features of severe asthma in humans.
Highlights
Many fibro-proliferative disorders of the lung such as asthma and chronic obstructive pulmonary disease (COPD) exhibit increased morbidity associated with mucus hypersecretion [1, 2]
We demonstrate that the intra-tracheal administration of TNF-like ligand 1A (TL1A) into the airways induces mucus production, and when blocking TL1A signaling through death receptor 3 (DR3), mucus production was abrogated in murine eosinophilic asthma
We have evidence that TL1A drives IL13 production by ILC2, which are increased in asthma
Summary
Many fibro-proliferative disorders of the lung such as asthma and chronic obstructive pulmonary disease (COPD) exhibit increased morbidity associated with mucus hypersecretion [1, 2]. Interleukin-13 (IL13) has recently emerged as a primary target for asthma therapy, with ongoing clinical trials targeting IL13 or approved therapeutics targeting its receptor interleukin-4 receptor a Abbreviations: IPF, Idiopathic pulmonary fibrosis; TNF, Tumor necrosis factor; TL1A, TNF-like ligand 1A; DR3, Death Receptor 3; ILC, Innate lymphoid cells; COPD, Chronic obstructive pulmonary disease; IL13, Interleukin 13; IL4Ra: Interleukin 4 receptor a; TNFSF15, Tumor necrosis factor superfamily member 15; ClcA1, Chloride channel regulator, Calcium-Activated-1; PAS, Periodic Acid-Schiff; H&E, Hematoxylin and Eosin; i.t., Intratracheal; i.n., Intranasal; i.p., Intraperitoneal
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