Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins

• Type of Material: Article
• Authors: Christopher Todd Capaldo, Emory University; Attila E. Farkas, Emory University; Roland Hilgarth, Emory University; Susanne M. Krug, Emory University; Mattie F. Wolf, Emory University; Jeremy K. Benedik, Emory University; Michael Fromm, Emory University; Michael Koval, Emory University; Charles Parkos, Emory University; Asma Nusrat, Emory University
• Language: English
• Date: 2014-09-15
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Capaldo et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E14-02-0773
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 25
• Issue: 18
• Start Page: 2710
• End Page: 2719
• Grant/Funding Information: Supported by the National Institutes of Health (DK64399 to C.A.P.; DK55679 and DK59888 to A.N.; HL116958 to M.K.; and DK64399 [National Institutes of Health DDRC grant]), Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute Comprehensive Cancer Center Grant P30CA138292, a Crohn's and Colitis Foundation of America Career Development award to C.T.C. and a fellowship award to A.E.F., and Deutsche Forschungsgemeinschaft FOR 721 TP-Z to S.M.K. and M.F.
• Keywords: HUMAN CYTOMEGALOVIRUS; CELL-LINE; INFLAMMATORY-BOWEL-DISEASE; PERMEABILITY; ZONULAE-OCCLUDENTES; NECROSIS-FACTOR-ALPHA; EXPRESSION; ULCERATIVE-COLITIS; Science & Technology; EPITHELIAL BARRIER FUNCTION; Cell Biology; Life Sciences & Biomedicine; INTERFERON-GAMMA
• Research Categories: Health Sciences, General; Health Sciences, Pathology

Abstract

Tight junctions (TJs) are dynamic, multiprotein intercellular adhesive contacts that provide a vital barrier function in epithelial tissues. TJs are remodeled during physiological development and pathological mucosal inflammation, and differential expression of the claudin family of TJ proteins determines epithelial barrier properties. However, the molecular mechanisms involved in TJ remodeling are incompletely understood. Using acGFP-claudin 4 as a biosensor of TJ remodeling, we observed increased claudin 4 fluorescence recovery after photobleaching (FRAP) dynamics in response to inflammatory cytokines. Interferon γ and tumor necrosis factor α increased the proportion of mobile claudin 4 in the TJ. Up-regulation of claudin 4 protein rescued these mobility defects and cytokine-induced barrier compromise. Furthermore, claudins 2 and 4 have reciprocal effects on epithelial barrier function, exhibit differential FRAP dynamics, and compete for residency within the TJ. These findings establish a model of TJs as self-assembling systems that undergo remodeling in response to proinflammatory cytokines through a mechanism of heterotypic claudin-binding incompatibility.