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

Abstract

BACKGROUND:

Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus defined by eosinophil infiltration and tissue remodeling with resulting symptoms of esophageal dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) promotes inflammation through upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2Ac, resulting in increased nuclear factor κB activation.

OBJECTIVE:

We sought to elucidate the role of TRAIL in EoE.

METHODS:

We used Aspergillus fumigatus to induce EoE in TRAIL-sufficient (wild-type) and TRAIL-deficient (TRAIL(-/-)) mice and targeted MID1 in the esophagus with small interfering RNA. We also treated mice with recombinant thymic stromal lymphopoietin (TSLP) and TRAIL.

RESULTS:

TRAIL deficiency and MID1 silencing with small interfering RNA reduced esophageal eosinophil and mast cell numbers and protected against esophageal circumference enlargement, muscularis externa thickening, and collagen deposition. MID1 expression and nuclear factor κB activation were reduced in TRAIL(-/-) mice, whereas protein phosphatase 2Ac levels were increased compared with those seen in wild-type control mice. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGFB, and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL(-/-) mice and recombinant TRAIL induced esophageal TSLP expression in vivo in the absence of allergen. Post hoc analysis of gene array data demonstrated significant upregulation of TRAIL and MID1 in a cohort of children with EoE compared with that seen in controls.

CONCLUSION:

TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy, and expression of inflammatory effector chemokines and cytokines in experimental EoE.

• Authors: Adam M Collison, Leon A Sokulsky, Joseph D Sherrill, Scott Nightingale, Luke Hatchwell, Nicholas J Talley, Marjorie M Walker, Marc E Rothenberg, Joerg Mattes
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 136 Issue 4 Pg. 971-82 (Oct 2015) ISSN: 1097-6825 [Electronic] United States
• PMID: 25981737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• NF-kappa B
• Proteins
• RNA, Small Interfering
• TNF-Related Apoptosis-Inducing Ligand
• Collagen
• Mid1 protein, mouse
• Ubiquitin-Protein Ligases
• Thymic Stromal Lymphopoietin

Topics

• Animals
• Aspergillus fumigatus (immunology)
• Cell Movement (genetics)
• Cells, Cultured
• Child
• Collagen (metabolism)
• Cytokines (genetics, metabolism)
• Eosinophilic Esophagitis (immunology)
• Eosinophils (drug effects, immunology)
• Esophagus (microbiology, pathology, physiology)
• Fibrosis
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Male
• Mast Cells (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Models, Animal
• NF-kappa B (genetics, metabolism)
• Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics)
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Ubiquitin-Protein Ligases
• Thymic Stromal Lymphopoietin