title: Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Podolsky
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Annette
authors.initials: A
authors.lastname: Eyking
authors.forename: Elke
authors.initials: E
authors.lastname: Cario
mesh_terms: D000818:Animals; D017209:Apoptosis; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009924:Organ Culture Techniques; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000071165:Trefoil Factor-3; D014945:Wound Healing
chemical_list: D008024:Ligands; D009077:Mucins; D011994:Recombinant Proteins; C493263:Tff3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D000071165:Trefoil Factor-3; D016264:Dextran Sulfate