TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis

Abstract

Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10 mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.

Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma

“…In same cases of refractory eosinophilic airway inflammation, increased drug delivery to the local inflammatory site with a novel method using inhaled ICS/LABA ETN has been shown to be effective [5]. Our findings are supported by recent reports showing that LABA ameliorates eosinophilic inflammation via PP2A activation [28,29].…”

Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

“…However, we, and others, have shown that TRAIL plays an important role in the pathogenesis of respiratory, [210][211][212] and more recently gastrointestinal, 213 tract disease. Significantly, we show that TRAIL plays an important role in early life Chlamydia infection-induced severe AAD in later life.…”

“…TRAIL is an immune factor that regulates inflammation and apoptosis and has largely been studied in the context of tumor immunology. However, we, and others, have shown that TRAIL plays an important role in the pathogenesis of respiratory, and more recently gastrointestinal, tract disease. Significantly, we show that TRAIL plays an important role in early life Chlamydia infection‐induced severe AAD in later life .…”

High‐fat diet‐induced obesity worsens TH2 immune response and immunopathologic characteristics in murine model of eosinophilic oesophagitis

“…At the 14th and 17th days of the allergy protocol, mice were orally challenged with a solution of 50 mg of OVA in 100 μL of sucralose thickened sterile saline, while the non‐allergic groups received a saline solution instead. Allergic groups had 1.5 g/L of OVA added to their water during the challenge . Euthanasia and sample collection were performed 24 hours after the last OVA challenge, and experimental design is shown in Figure A.…”