Hiroo Tanaka1, Maki Takechi1, Hiroshi Kiyonari2, Go Shioi2, Atsushi Tamura1, Sachiko Tsukita1. 1. Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 2. Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.
Abstract
OBJECTIVE: To design novel anti-inflammation treatments, it is important to recognise two distinct steps of inflammation: initiation and acceleration. In IBDs, intestinal inflammation is reported to be accelerated by dysfunction in the epithelial paracellular barrier formed by tight junctions (TJs). However, it is unclear whether changes in paracellular barrier function initiate inflammation. Some of the intestinal claudin-family proteins, which form the paracellular barrier, show aberrant expression levels and localisations in IBDs. We aimed to elucidate the role of paracellular-barrier change in initiating colonic inflammation. DESIGN: We generated intestine-specific conditional knockout mice of claudin-7 (Cldn7), one of the predominant intestinal claudins. RESULTS: The intestine-specific Cldn7 deficiency caused colonic inflammation, even though TJ structures were still present due to other claudins. The paracellular flux (pFlux), determined by measuring the paracellular permeability across the colon epithelium, was enhanced by the Cldn7 deficiency for the small organic solute Lucifer Yellow (457 Da), but not for the larger organic solute FITC-Dextran (4400 Da). Consistent with these results, the intestine-specific claudin-7 deficiency enhanced the pFlux for N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) (438 Da), a major bacterial product, to initiate colonic inflammation. CONCLUSIONS: These findings suggest that specific enhancement of the pFlux for small organic solutes across the claudin-based TJs initiates colonic inflammation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: To design novel anti-inflammation treatments, it is important to recognise two distinct steps of inflammation: initiation and acceleration. In IBDs, intestinal inflammation is reported to be accelerated by dysfunction in the epithelial paracellular barrier formed by tight junctions (TJs). However, it is unclear whether changes in paracellular barrier function initiate inflammation. Some of the intestinal claudin-family proteins, which form the paracellular barrier, show aberrant expression levels and localisations in IBDs. We aimed to elucidate the role of paracellular-barrier change in initiating colonic inflammation. DESIGN: We generated intestine-specific conditional knockout mice of claudin-7 (Cldn7), one of the predominant intestinal claudins. RESULTS: The intestine-specific Cldn7 deficiency caused colonic inflammation, even though TJ structures were still present due to other claudins. The paracellular flux (pFlux), determined by measuring the paracellular permeability across the colon epithelium, was enhanced by the Cldn7 deficiency for the small organic solute Lucifer Yellow (457 Da), but not for the larger organic solute FITC-Dextran (4400 Da). Consistent with these results, the intestine-specific claudin-7 deficiency enhanced the pFlux for N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) (438 Da), a major bacterial product, to initiate colonic inflammation. CONCLUSIONS: These findings suggest that specific enhancement of the pFlux for small organic solutes across the claudin-based TJs initiates colonic inflammation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Nicolas Montalbetti; Anna C Rued; Dennis R Clayton; Wily G Ruiz; Sheldon I Bastacky; H Sandeep Prakasam; Amity F Eaton; F Aura Kullmann; Gerard Apodaca; Marcelo D Carattino Journal: Am J Physiol Renal Physiol Date: 2015-09-30
Authors: Thanh Q Dang; Nanyoung Yoon; Helen Chasiotis; Emily C Dunford; Qilong Feng; Pingnian He; Michael C Riddell; Scott P Kelly; Gary Sweeney Journal: J Endocrinol Date: 2017-08 Impact factor: 4.286