title: Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis.
abstract: Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4-/- and MyD88-/- mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4-/- mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4-/- mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88-/- mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4-/- and MyD88-/- mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4-/- and MyD88-/- mice. The similarity in crypt epithelial damage between TLR4-/- or MyD88-/- and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Ave., 11-23D, Box 1069, New York, New York 10029, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Michelsen
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Eri
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Thomas
authors.forename: Bing
authors.initials: B
authors.lastname: Hu
authors.forename: Katie
authors.initials: K
authors.lastname: Lukasek
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.forename: Juan
authors.initials: J
authors.lastname: Lechago
authors.forename: Ruliang
authors.initials: R
authors.lastname: Xu
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.forename: Antoine
authors.initials: A
authors.lastname: Soliman
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000494:pharmacology; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D009504:Neutrophils / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016264:Dextran Sulfate