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

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• 作者：Adam M. Collison ; PhD^a ; ^b ; ^&lowast ; ; ^{Adam.Collison@newcastle.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Leon A. Sokulsky ; BBiomedSci (Hons)^a ; ^b ; ^&lowast ; ; Joseph D. Sherrill ; PhD^e ; Scott Nightingale ; BMed (Hons) ; MClinEpid ; FRACP^c ; ^d ; Luke Hatchwell ; BBiomedSci (Hons)^a ; ^b ; Nicholas J. Talley ; MD ; PhD^d ; Marjorie M. Walker ; FRCPath^d ; Marc E. Rothenberg ; MD ; PhD^e ; Joerg Mattes ; MD ; PhD^a ; ^b ; ^d ; ^f
• 关键词：Eosinophilic esophagitis ; allergy ; tissue remodeling ; fibrosis ; cytokine ; TNF-related apoptosis-inducing ligand ; midline-1 ; protein phosphatase 2Ac ; nuclear factor 魏B ; thymic stromal lymphopoietin ; IL-25 ; CCL20 ; CCL24 ; CCL11
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：136
• 期：4
• 页码：971-982
• 全文大小：3827 K

文摘

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 魏B 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 魏B 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.