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INFLAMMATION/IMMUNITY/MEDIATORS
1Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, and 5Department of Pathology, Mount Sinai School of Medicine, New York, New York; 3Inflammatory Bowel Disease Center, 2Division of Pediatric Infectious Diseases, Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, and 4Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
Submitted 26 July 2004 ; accepted in final form 24 November 2004
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.
neutrophil chemotaxis; dextran sodium sulfate; inflammatory bowel disease; innate immunity
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