Colitis-Associated Variant of TLR2 Causes Impaired Mucosal Repair Because of TFF3 Deficiency

Daniel K. Podolsky, Guido Gerken, Annette Eyking, Elke Cario

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Background & Aims: Goblet cells (GC) facilitate mucosal protection and epithelial barrier repair, yet the innate immune mechanisms that selectively drive GC functions have not been defined. The aim of this study was to determine whether Toll-like receptor (TLR) 2 and modulation of GC-derived trefoil factor (TFF) 3 are functionally linked in the intestine. Methods: GC modulation was assessed using quantitative real-time polymerase chain reaction analysis (qRT-PCR), Western blotting, and confocal microscopy. Dextran sulfate sodium (DSS) colitis was induced in wild-type, TFF3-/-, and TLR2-/- mice. Recombinant TLR2 ligand or TFF3 peptide were orally administered after DSS termination. Caco-2 cells overexpressing full-length TLR2 or mutant TLR2-R753Q were tested for TFF3 synthesis and functional-related effects in a wounding assay. Results: Data from in vitro (Ls174T) and ex vivo models of murine and human GC reveal that TLR2 activation selectively induces synthesis of TFF3. In vivo studies using TFF3-/- or TLR2-/- mice demonstrate the ability for oral treatment with a TLR2 agonist to confer antiapoptotic protection of the intestinal mucosa against inflammatory stress-induced damage through TFF3. Recombinant TFF3 rescues TLR2-deficient mice from increased morbidity and mortality during acute colonic injury. Severe ulcerative colitis (UC) has recently been found to be associated with the R753Q polymorphism of the TLR2 gene. The relevance of the observed functional effect of TLR2 in regulating GC is confirmed by the finding that the UC-associated TLR2-R753Q variant is functionally deficient in the ability to induce TFF3 synthesis, thus leading to impaired wound healing. Conclusions: These data demonstrate a novel function of TLR2 in intestinal GC that links products of commensal bacteria to innate immune protection of the host via TFF3.

Original languageEnglish (US)
Pages (from-to)209-220
Number of pages12
JournalGastroenterology
Volume137
Issue number1
DOIs
StatePublished - Jul 2009

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Goblet Cells
Colitis
Dextran Sulfate
Ulcerative Colitis
Toll-Like Receptor 2
Caco-2 Cells
Intestinal Mucosa
Confocal Microscopy
Wound Healing
Intestines
Real-Time Polymerase Chain Reaction
Western Blotting
Ligands
Morbidity
Bacteria
Mortality
Wounds and Injuries
Genes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Colitis-Associated Variant of TLR2 Causes Impaired Mucosal Repair Because of TFF3 Deficiency. / Podolsky, Daniel K.; Gerken, Guido; Eyking, Annette; Cario, Elke.

In: Gastroenterology, Vol. 137, No. 1, 07.2009, p. 209-220.

Research output: Contribution to journalArticle

Podolsky, Daniel K. ; Gerken, Guido ; Eyking, Annette ; Cario, Elke. / Colitis-Associated Variant of TLR2 Causes Impaired Mucosal Repair Because of TFF3 Deficiency. In: Gastroenterology. 2009 ; Vol. 137, No. 1. pp. 209-220.
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