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J. Biol. Chem. 284 (33): 22332-22343

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury*Formula

Birgit Ey{ddagger}1, Annette Eyking{ddagger}1, Guido Gerken{ddagger}, Daniel K. Podolsky§, , and Elke Cario{ddagger}2

From the {ddagger}Division of Gastroenterology and Hepatology, University Hospital of Essen, and Medical School, University of Duisburg-Essen, 45147 Essen, Germany and
the §Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

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Abstract: Gap junctional intercellular communication (GJIC) coordinates cellular functions essential for sustaining tissue homeostasis; yet its regulation in the intestine is not well understood. Here, we identify a novel physiological link between Toll-like receptor (TLR) 2 and GJIC through modulation of Connexin-43 (Cx43) during acute and chronic inflammatory injury of the intestinal epithelial cell (IEC) barrier. Data from in vitro studies reveal that TLR2 activation modulates Cx43 synthesis and increases GJIC via Cx43 during IEC injury. The ulcerative colitis-associated TLR2-R753Q mutant targets Cx43 for increased proteasomal degradation, impairing TLR2-mediated GJIC during intestinal epithelial wounding. In vivo studies using mucosal RNA interference show that TLR2-mediated mucosal healing depends functionally on intestinal epithelial Cx43 during acute inflammatory stress-induced damage. Mice deficient in TLR2 exhibit IEC-specific alterations in Cx43, whereas administration of a TLR2 agonist protects GJIC by blocking accumulation of Cx43 and its hyperphosphorylation at Ser368 to prevent spontaneous chronic colitis in MDR1{alpha}-deficient mice. Finally, adding the TLR2 agonist to three-dimensional intestinal mucosa-like cultures of human biopsies preserves intestinal epithelial Cx43 integrity and polarization ex vivo. In conclusion, Cx43 plays an important role in innate immune control of commensal-mediated intestinal epithelial wound repair.

Abbreviations: IEC, intestinal epithelial cell(s) • Cx43, connexin-43 • DSS, dextran sodium sulfate • GJ, gap junction • GJIC, gap junctional intercellular communication • MDR1, multidrug resistance gene • TJ, tight junction • TLR, Toll-like receptor • UC, ulcerative colitis • WT, wild type • ZO-1, zonula occludens-1 • PCSK, Pam3CysSK4 • HA, hemagglutinin • FL, full-length • FITC, fluorescein isothiocyanate • DAPI, 4',6-diamidino-2-phenylindole • siRNA, small interfering RNA • RT, reverse transcription • GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Received for publication March 10, 2009.

1 These authors contributed equally to this work.

2 To whom correspondence should be addressed: Div. of Gastroenterology and Hepatology, University Hospital of Essen, Ig I, Virchowstr. 171, 45147 Essen, Germany. Tel/Fax.: 49-201-723-4527; E-mail: elke.cario{at}uni-due.de.

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