TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis

Abstract

Background Eosinophilic Oesophagitis (EoE) is an inflammatory disorder of the oesophagus defined by eosinophil infiltration and tissue remodelling with resulting symptoms of oesophageal dysfunction. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes inflammation by upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2 A (PP2Ac) resulting in increased NF-κB activation. Objective To elucidate the role of TRAIL in EoE. Methods We used Aspergillus fumigatus(Asp F) to induce EoE in TRAIL sufficient (wildtype) and deficient (−/−) mice and targeted MID1 in the oesophagus with small interfering (si) RNA. We also treated mice with recombinant TSLP and TRAIL. Results TRAIL deficiency and MID1 silencing employing siRNA reduced oesophageal eosinophil and mast cell numbers and protected from oesophageal circumference enlargement, muscularis externa thickening and collagen deposition. MID1 expression and NF-κB activation were reduced in TRAIL−/− mice, while PP2Ac levels were increased compared to wildtype controls. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGF-β and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL−/− mice and recombinant TRAIL induced oesophageal TSLP expression in vivo in the absence of allergen. Post hoc analysis of gene array data demonstrated a significant upregulation of TRAIL and MID1 in a cohort of children with EoE as compared to diseased controls. Conclusion TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy and expression of inflammatory effector chemokines and cytokines in experimental EoE.

The Immunologic Mechanisms of Eosinophilic Esophagitis

“…TSLP is overexpressed in esophageal biopsies from individuals with EoE as compared to unaffected individuals, while WDR36 expression is unaltered, implicating the 5q22 locus (and TSLP in particular) in the pathogenesis of EoE [48]. Animal models also support a role for TSLP in EoE pathogenesis [150•]. In a murine epicutaneous sensitization model of EoE, esophageal inflammation is dependent in part of TSLP and basophils, but independent of IgE.…”

TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection

“…inflammation of the esophagus (17). In allergic disease settings, we observed that Tnfsf10 Ϫ/Ϫ mice were protected from AHR associated with reduced mast cell numbers and eosinophilic inflammation (14,60).…”

“…It is not yet known if TRAIL modulates apoptosis during RV infection in vivo, or whether it has any effect on virus replication and/or inflammation. It was shown previously that TRAIL promoted inflammatory responses in the context of allergic inflammation of the lung and esophagus, neonatal Chlamydia infection, and cigarette smoke-induced COPD (14,15,17,31,53,60).…”

Novel mTORC1 Mechanism Suggests Therapeutic Targets for COMPopathies

“…42,53 TNFa/TRAIL drive MID1 expression in asthma and esophageal eosinophilia. 54,55 It was determined whether TNFa increases Trail and Mid1 independent of MT-COMP expression in RCS cells, as this TNFa increase in MID1 was previously shown in the epithelial cells lining the airway. 55 TNFa treatment (200 ng/mL) in RCS cells for 72 hours increased both Trail and Mid1 mRNAs by 33-and 16-fold, respectively ( Figure 3K).…”

“…54,55 It was determined whether TNFa increases Trail and Mid1 independent of MT-COMP expression in RCS cells, as this TNFa increase in MID1 was previously shown in the epithelial cells lining the airway. 55 TNFa treatment (200 ng/mL) in RCS cells for 72 hours increased both Trail and Mid1 mRNAs by 33-and 16-fold, respectively ( Figure 3K). Consistent with these findings, both TNFa and TRAIL immunostaining were also increased in MT-COMP mice compared to controls (Figure 3, AeJ).…”