What are toll-like receptors and what role may they have in IBD?

The immune system can be divided into innate and adaptive components. The more recently understood innate immune system serves to immediately recognize pathogenassociated molecular patterns (PAMPs) and control infection through elaboration of proinflammatory cytokines and chemokines that recruit inflammatory cells such as neutrophils and monocytes. It is responsible for containing an infection until the adaptive immune system can orchestrate an antigenspecific immune response with T cells and B cells. Innate immune recognition relies on germline-encoded receptors that recognize a limited number of highly conserved structures found exclusively in microbial pathogens. Among these germline-encoded pathogen-recognition receptors, Toll-like receptors (TLRs) are members of a conserved interleukin-1 (IL-1) superfamily of transmembrane receptors that recognize PAMPs. A total of 13 TLRs have been described, although some of the ligands for these TLRs have not been determined. The spectrum of pathogens recognized by TLRs includes Gram-positive and Gram-negative bacteria, yeast, and viruses. As an example, TLR4 interacts with lipopolysaccharide (LPS), resulting in the recruitment of the adapter molecule MyD88, phosphorylation of the IL-1 receptor-associated kinase (IRAK) followed by tumor necrosis factor (TNF) receptor-a associated factor 6 (TRAF6). Most TLRs use MyD88 as an adapter molecule, although other adapter molecules such as TRIF are utilized by TLR3. Recruitment of TRAF6 leads to the phosphorylation of I Bkinases and release of NFB as well as activation of the mitogen activated protein kinase (MAPK) pathway. The activation of NFB triggers a potent proinflammatory response in most cell types expressing TLRs. Given the complexity of the commensal flora, the question then becomes, how does the intestinal mucosa regulate TLR signaling? In particular, how does TLR signaling discriminate between commensal and pathogenic bacteria? The expression and function of several TLRs have been examined in the intestine. In general, TLR expression by intestinal epithelial cells is low compared with hematopoietic cells such as macrophages. Human intestinal epithelial cells normally express TLR3 and TLR5, while TLR2 and TLR4 are only barely detectable .1–4 However, TLR4 is up regulated in both Crohn’s disease (CD) and ulcerative colitis (UC), while the expression of TLR2 and TLR5 remains unchanged.5–7 Inflammatory cytokines such as IFNand TNFincrease expression of TLR4 and MD-2, resulting in increased LPS responsiveness.4,8 In addition, expression of TLR4 and TLR2 is increased in lamina propria macrophages in IBD.5 The observation that expression of certain TLRs is increased in inflammatory bowel disease (IBD) may be a secondary event because of the presence of inflammatory mediators. Nevertheless, the increased expression of TLRs may result in inadvertent hyperreactivity to the commensal flora. It is also possible that a subset of IBD patients is characterized by dysregulated, constitutively active TLR signaling. On the flip side of implicating increased TLR signaling as propagating or contributing to inflammation, decreased TLR signaling might also play a detrimental role in IBD. First, polymorphisms in TLR genes have been associated with IBD.9 Two missense mutations in the extracellular domain of TLR4 have been associated with hyporesponsiveness to inhaled LPS and protection against atherosclerosis. The association with IBD is not as straightforward, with 1 study showing a positive association with UC,10 another showing a positive association with both CD and UC,11 and another showing no association with CD.12 A large consortium of American and Canadian investigators has found a positive association of TLR4 polymorphisms with Crohn’s disease (odds ratio 1.33).13 Polymorphisms in TLR9 have also been linked with CD.14 These data could be considered along with the known association of CD with mutations in the Nod2/ CARD15 gene, namely deficient innate immune responses may play a role in IBD susceptibility. Multiple models could be drawn as to how defective TLR responsiveness could lead to IBD susceptibility. TLR5 / mice are more susceptible to spontaneous and induced colitis.15 In this regard, TLR4 has been most studied with respect to its function in animal models of inflammation. TLR4 appears to be important for healing of the injured intestinal epithelium.16 We and others have described decreased epithelial proliferation in TLR4 or MyD88-deficient mice.16–18 These data suggest a role for TLR4 in regulation of intestinal epithelial cell proliferation. MyD88-deficient mice From the Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Florida, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20632 Published online in Wiley InterScience (www.interscience.wiley.com).