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

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TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis Adam M. Collison, PhD, Leon A. Sokulsky, BBiomedSci (Hons), Joseph D. Sherrill, PhD, Scott Nightingale, BMed (Hons), MClinEpid, FRACP, Luke Hatchwell, BBiomedSci (Hons), Nicholas J. Talley, MD, PhD, Marjorie M. Walker, FRCPath, Marc E. Rothenberg, MD, PhD, Joerg Mattes, MD, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 971-982 (October 2015) DOI: 10.1016/j.jaci.2015.03.031 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 The TRAIL signaling pathway is active in EoE. A and B, Individual fragments per kilobase of transcript per million mapped reads (FPKM) values of TNFSF10 (TRAIL; Fig 1, A) and MID1 (Fig 1, B) from RNA sequencing performed on esophageal biopsy specimens from healthy control subjects (NL; n = 6) and patients with active EoE (n = 10). C and D, Mouse MID1 (Fig 1, C) and PP2Ac (Fig 1, D) protein levels from esophagi of A fumigatus (Asp F)–treated and saline control (SAL) mice, as assessed by using ELISA. E, Activity assay for the NF-κB subunit p65. F-H, Histologic enumeration of esophageal eosinophils using chromatin stain (Fig 1, F), mast cell infiltration using toludine blue (Fig 1, G), and eosinophilia in the blood determined by using Giemsa stain (Fig 1, H). I, Esophageal T cells (TCR+CD4+), as enumerated by means of fluorescence-activated cell sorting. Data are expressed as means ± SEMs. *P < .05 and ***P < .005. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TRAIL regulates PP2Ac and p65 activity in addition to eosinophil and mast cell infiltration. A, MID1 expression was determined by using quantitative PCR. Gene expression was normalized to the copy number of ACTB. B and C, Protein expression of PP2Ac (Fig 2, B) and p65 activity (Fig 2, C). D, Histologic enumeration of esophageal eosinophils using chromatin stain. E, Enumeration of mast cells stained with toludine blue. F, Eosinophilia in the blood determined by using Giemsa stain. G, Differential cell count of total cells isolated from mice through bronchoalveolar lavage. BALF, Bronchoalveolar lavage fluid. *P < .05. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Inflammatory and remodeling cytokines involved in EoE are regulated by TRAIL. A-D and G, Expression of CCL11 (Fig 3, A), CCL24 (Fig 3, B), TGFB (Fig 3, C), TSLP (Fig 3, D), and STAT6 (Fig 3, G) was determined by using quantitative RT-PCR. Gene expression was normalized to copy numbers of ACTB. E and F, IL-5 (Fig 3, E) and IL-13 (Fig 3, F) protein expression was determined by using ELISA. *P < .05. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Esophageal remodeling in EoE is dependent on TRAIL expression. A, Representative images of transverse esophageal sections at ×100 and ×200 magnification (stained with Masson trichrome) from WT and TRAIL−/− mice challenged with A fumigatus or saline control. B-D, Muscularis externa (Fig 4, B), esophageal circumference (Fig 4, C), and subepithelial collagen deposition (Fig 4, D), as determined with Image-Pro Plus analysis (n = 5-6). *P < .05. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 TSLP is sufficient to restore A fumigatus–induced remodeling in TRAIL−/− mice. A, Representative images of transverse esophageal sections at ×100 and ×200 magnification (stained with Masson trichrome) from TRAIL−/− mice challenged with A fumigatus and treated with recombinant TSLP or vehicle control. B, Histologic enumeration of esophageal eosinophils using chromatin staining. C, TSLP expression in esophagi of WT mice after treatment with recombinant TRAIL or saline control determined by using quantitative PCR. Gene expression was normalized to copy numbers of ACTB. D-F, Muscularis externa (Fig 5, D), esophageal circumference (Fig 5, E), and subepithelial collagen deposition (Fig 5, F), as determined with Image-Pro Plus analysis (n = 6-8). *P < .05 and **P < .01. Asp F, A fumigatus; SAL, saline; VEH, vehicle control. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Esophageal remodeling in EoE is dependent on MID1. A, Representative images of transverse esophageal sections at ×100 and ×200 magnification (stained with Masson trichrome) from WT mice challenged with A fumigatus and treated with siRNA targeting MID1, nonsense siRNA, or saline control. B, Esophageal MID1 expression determined by using quantitative PCR. Gene expression was normalized to copy numbers of ACTB. C, Histologic enumeration of esophageal eosinophils using chromatin stain. D-F, Muscularis externa (Fig 6, D), esophageal circumference (Fig 6, E), and subepithelial collagen deposition (Fig 6, F), as determined with Image-Pro Plus analysis (n = 8). *P < .05, **P < .01, ***P < .005, and ****P < .0001. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 MID1 regulates a subset of TRAIL-regulated inflammatory cytokines in EoE. Expression of CCL11 (A), CCL24 (B), TGFB (C), and TSLP (D) was determined by using quantitative RT-PCR. Gene expression was normalized to copy numbers of ACTB (n = 8). *P < .05 and **P < .01. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 TRAIL and IL-25 expression is highest during establishment of the A fumigatus EoE model. A and B, Representative immunofluorescence images of esophageal sections counterstained with 4′-6-diamidino-2-phenylindole dihydrochloride and stained with phycoerythrin-conjugated isotype control (Fig 8, A) and phycoerythrin-conjugated anti-TRAIL N2B2 antibody (Fig 8, B). C-J, Expression of TRAIL (Fig 8, C and H), MID1 (Fig 8, D), IL-25 (Fig 8, F and J), CCL20 (Fig 8, E and I), and TSLP (Fig 8, G) was determined by using quantitative PCR after 24 hours (Fig 8, C-G) and 3 weeks (Fig 8, H-J) of A fumigatus challenges. Gene expression was normalized to copy numbers of ACTB (n = 7-9). *P < .05 and **P < .01. Asp F, A fumigatus; SAL, saline. Journal of Allergy and Clinical Immunology 2015 136, 971-982DOI: (10.1016/j.jaci.2015.03.031) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions