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.

Cox-2 Is Regulated by Toll-Like Receptor-4 (TLR4) Signaling: Role in Proliferation and Apoptosis in the Intestine

“…We and others have used an acute model of colitis to address the function of TLR4 in the setting of epithelial injury and inflammation. Administration of DSS to animals genetically deficient in TLR4 or MyD88 results in greater toxicity manifested by increased rectal bleeding, weight loss and mortality compared to wild-type littermates [14][15][16] . We have also found that animals deficient in TLR4 or MyD88 have decreased neutrophil recruitment to the intestine due to defective expression of chemokines and they experience bacterial translocation to mesenteric lymph nodes 15 .…”

Toll-Like Receptor Signaling in Small Intestinal Epithelium Promotes B-Cell Recruitment and IgA Production in Lamina Propria

“…However, TLR4 signaling in response to pathogenic infection results in intestinal epithelial chemokine expression and the recruitment of inflammatory cells and intraepithelial dendritic cells 15-17 . We and others have explored the role of TLR4 in intestinal epithelial homeostasis and defense against pathogens. TLR4 knockout mice develop worse clinical symptoms of colitis following injury with dextran sodium sulfate (DSS) 18,19 . Underlying this phenotype, TLR4 knockout mice have decreased intestinal epithelial cell proliferation, decreased recruitment of inflammatory cells, and increased bacterial translocation to mesenteric lymph nodes 18 .…”

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

“…An allele of murine TLR4, Lpsd, was first noted to decrease the severity of experimental colitis induced by dextran sulfate sodium (DSS), 6 and more recently, TLR4 À/À and MyD88 À/À mice have been shown to have more severe DSS-induced colitis than their wild-type littermates. [7][8][9] In addition, mutations in CARD15/NOD2 have been associated with susceptibility to human CD [10][11][12] and shown to affect nuclear factor-kB (NF-kB) activation, interleukin (IL)-1b processing, and resistance to intestinal Listeria monocytogenes infection in mice. 13,14 Within the TLR family of PRR, there are 10 different transmembrane receptors (TLR1-10) that are found either on the extracellular surface of cells (TLR1, 2 and 4) or within intracellular compartments such as endosomes (TLR3 and 7-9).…”