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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 JCI+Insight
2016 ; 1
(4
): e86355
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Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that
mediates esophageal epithelial barrier impairment
#MMPMID27158675
Davis BP
; Stucke EM
; Khorki ME
; Litosh VA
; Rymer JK
; Rochman M
; Travers J
; Kottyan LC
; Rothenberg ME
JCI Insight
2016[Apr]; 1
(4
): e86355
PMID27158675
show ga
We recently identified a genome-wide genetic association of eosinophilic
esophagitis (EoE) at 2p23 spanning the calpain 14 (CAPN14) 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 CAPN14 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 CAPN14 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 CAPN14 by IL-13 and genetic linkage of EoE to the CAPN14 gene
locus, demonstrate a molecular and cellular pathway that contributes to T helper
type 2 responses in mucosal epithelium.