Journal article
Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment
JCI insight, Vol.1(4), pp.e86355-e86355
04/2016
DOI: 10.1172/jci.insight.86355
PMCID: PMC4855700
PMID: 27158675
Abstract
We recently identified a genome-wide genetic association of eosinophilic esophagitis (EoE) at 2p23 spanning the calpain 14 (
) gene, yet the causal mechanism has not been elucidated. We now show that recombinant CAPN14 cleaves a calpain-specific substrate and is inhibited by 4 classical calpain inhibitors: MDL-28170, acetyl-calpastatin, E-64, and PD151746. CAPN14 is specifically induced (>100-fold) in esophageal epithelium after IL-13 treatment. Epithelial cells overexpressing CAPN14 display impaired epithelial architecture, characterized by acantholysis, epidermal clefting, and epidermolysis. CAPN14 overexpression impairs epithelial barrier function, as demonstrated by decreased transepithelial resistance (2.1-fold) and increased FITC-dextran flux (2.6-fold). Epithelium with gene-silenced
demonstrates increased dilated intercellular spaces (5.5-fold) and less organized basal cell layering (1.5-fold) following IL-13 treatment. Finally, CAPN14 overexpression results in loss of desmoglein 1 (DSG1) expression, whereas the IL-13-induced loss of DSG1 is normalized by
gene silencing. Importantly, these findings were specific to CAPN14, as they were not observed with modulation of CAPN1 expression. These results, along with the potent induction of
by IL-13 and genetic linkage of EoE to the
gene locus, demonstrate a molecular and cellular pathway that contributes to T helper type 2 responses in mucosal epithelium.
Details
- Title: Subtitle
- Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment
- Creators
- Benjamin P Davis - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAEmily M Stucke - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAM Eyad Khorki - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAVladislav A Litosh - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAJeffrey K Rymer - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAMark Rochman - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAJared Travers - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USALeah C Kottyan - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAMarc E Rothenberg - Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.1(4), pp.e86355-e86355
- DOI
- 10.1172/jci.insight.86355
- PMID
- 27158675
- PMCID
- PMC4855700
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- U19 AI070235 / NIAID NIH HHS R01 AI124355 / NIAID NIH HHS P30 DK078392 / NIDDK NIH HHS T32 AI060515 / NIAID NIH HHS
- Language
- English
- Date published
- 04/2016
- Academic Unit
- Stead Family Department of Pediatrics; Immunology; Internal Medicine
- Record Identifier
- 9984093470902771
Metrics
15 Record Views