Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis

Masayuki Fukata, Kathrin S. Michelsen, Rajaraman Eri, Lisa S. Thomas, Bing Hu, Katie Lukasek, Cynthia C. Nast, Juan Lechago, Ruliang Xu, Yoshikazu Naiki, Antoine Soliman, Moshe Arditi, Maria T Abreu

Research output: Contribution to journalArticle

374 Citations (Scopus)

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 down-stream 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume288
Issue number5 51-5
DOIs
StatePublished - May 1 2005
Externally publishedYes

Fingerprint

Bacterial Translocation
Toll-Like Receptor 4
Colitis
Differentiation Antigens
Wounds and Injuries
Dextran Sulfate
Bacteria
Innate Immunity
Macrophages
Chemokine CXCL2
Hemorrhage
Mucosal Immunity
Neutrophil Infiltration
Gram-Negative Bacteria
Inflammatory Bowel Diseases
Chemokines
Knockout Mice
Weight Loss
Mucous Membrane
Lymph Nodes

Keywords

  • Dextran sodium sulfate
  • Inflammatory bowel disease
  • Innate immunity
  • Neutrophil chemotaxis

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. / Fukata, Masayuki; Michelsen, Kathrin S.; Eri, Rajaraman; Thomas, Lisa S.; Hu, Bing; Lukasek, Katie; Nast, Cynthia C.; Lechago, Juan; Xu, Ruliang; Naiki, Yoshikazu; Soliman, Antoine; Arditi, Moshe; Abreu, Maria T.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 288, No. 5 51-5, 01.05.2005.

Research output: Contribution to journalArticle

Fukata, Masayuki ; Michelsen, Kathrin S. ; Eri, Rajaraman ; Thomas, Lisa S. ; Hu, Bing ; Lukasek, Katie ; Nast, Cynthia C. ; Lechago, Juan ; Xu, Ruliang ; Naiki, Yoshikazu ; Soliman, Antoine ; Arditi, Moshe ; Abreu, Maria T. / Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2005 ; Vol. 288, No. 5 51-5.
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AU - Lechago, Juan

AU - Xu, Ruliang

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