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

Abstract

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.

TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3‐mediated A1 differentiation of astrocytes

“…It has been found to act importantly in inflammatory bowel disease, neuroimmunity, and neuroinflammation 10 . Besides, TL1A can mediate the activation of downstream signals like NLRP3 through TNFRs 11 . NLRP3 plays a positive regulatory role in the A1 differentiation of RAs, 12 while it remains unknown whether TL1A is associated with the RA differentiation.…”

Suppression of SPARC Ameliorates Ovalbumin-induced Airway Remodeling via TGFβ1/Smad2 in Chronic Asthma

“…Airway resistance of mice was measured within 24 hours after the last challenge, and the assessment methods were performed as previously described by our research team. 19 All mice were euthanized 24 hours after the last exposure.…”

Research progress on the relationship between Paneth cells-susceptibility genes, intestinal microecology and inflammatory bowel disease

“…Similarly, PC-specific clearance of XBP1 can produce similar symptoms of spontaneous ileitis, suggesting that the PC-specific UPR plays an important role in maintaining ileal mucosal homeostasis in mice[ 124 ]. Xbp1 knockout in the mouse epithelium resulted in spontaneous enteritis in mice[ 125 ]. Pathological analysis showed that the deletion of Xbp1 resulted in endoplasmic reticulum stress and a lack of lysozyme and α-defensin expression in PCs[ 125 ].…”

“…Xbp1 knockout in the mouse epithelium resulted in spontaneous enteritis in mice[ 125 ]. Pathological analysis showed that the deletion of Xbp1 resulted in endoplasmic reticulum stress and a lack of lysozyme and α-defensin expression in PCs[ 125 ]. Therefore, XBP1 may play a partially compensatory role in inhibiting proinflammatory signals, maintaining mucosal homeostasis and assisting PC function in mice, thus supporting the function of PCs[ 126 ].…”