PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. It's a Gut Reaction: Innate Immunity and the Development of Gut Inflammatory Disease by Paul D. Rennert The interaction of the self with the environment provides continuous opportunity for the immune system to respond to antigens in a way that can become detrimental. One obvious example is inflammatory bowel disease (IBD), in which a chronic inflammatory response to gut antigen leads to destruction of the mucosal tissues of the gastrointestinal tract. In animal models there are two well known ways to trigger IBD: one is to damage the mucosal tissue directly, using chemical insults, the second is to perturb the normal function of T cells, using transgenic mice, gene-deficient mice, or T cell adoptive transfer models (G. Bouma & W. Strober, Nat Rev Immunol 3, 521 (2003). These are very different approaches, but they can be linked by consideration of the function of the innate immune system, which ties pathogen recognition at the level of the environment (in this case, the gut lumen) to activation of the adaptive immune system and the recruitment of lymphocytes. Chronic activation of lymphocytes infiltrating the damaged tissue results in further tissue destruction, thereby further promoting the disease. Innate immune receptors include the Toll-like receptors (TLRs) and other proteins that recognize microorganism-derived antigens. In the gut setting TLRs have to recognize and respond to both commensal bacteria and pathogenic bacteria in a manner that prevents infection, but does not damage the mucosal tissue. Ulcerative colitis (UC) and Crohn's disease (CD) are 2 subtypes of IBD, that differ in the extent of GI tract involvement, some clinical features, and the type of T cell effector cell response (Th1 or Th2, respectively). Both diseases are considered to be the result of an uncontrolled mucosal immune response to bacterial antigens. Remarkable progress has recently been made identifying mechanisms that normally control mucosal innate immunity, and a few examples will be the subject of this review. One intensely studied system involves the NOD2 gene product, and its role in controlling the immune response to the bacterial antigen muramyl dipeptide (MDP), a component of bacterial cell walls. NOD2 was originally identified as a CD susceptibility gene (J. P. Hugot et al., Nature 411, 599 (2001), Y. Ogura et al., Nature 411, 603 (2001) although its function has remained obscure. Very recently however, genetic models of a NOD2 mutation commonly found in CD, as well as analyses of a NOD2-deficient mouse, have shed new light on this pathway, and suggest that NOD2 functions by sensing foreign antigen (MDP), and inducing an appropriate immune response by activating NF-kB. The CD-associated mutations found in human patients, therefore, are gain-of-function mutations that lead to excessive NF-kB activation and chronic inflammation (K. S. Kobayashi et al., Science 307, 731 (2005), S. Maeda et al., Science 307, 734 (2005). What is striking about this model is that excessive NF-kB activation is known to drive inflammation by triggering secretion of pro-inflammatory cytokines (TNF, IL-1b) and other cell activators, which can activate the adaptive immune system and recruit lymphocytes to the site of inflammation. NF-kB also supports cell survival by inducing expression of anti-apoptotic facotrs that prevent activation-induced and other forms of cell death. Other innate immunity pathways have been implicated in the development of IBD, suggesting that disregulated innate immunity is recurrent cause of these diseases. TLR5 is known to recognize bacterial flagellins, which are common proteins of motile bacteria. Recently it was demonstrated that specific flagellins constitute a major target of the T and B cell response in mouse models of IBD as well as in a subset of patients with CD (M. L. Lodes et al., J Clin Med 113, 1296 (2004). This identifies the flagellin/TLR5 recognition step as a potential trigger leading to abberant recognition of flagellin by T cells, causing chronic inflammation. B cell-derived anti-flagellin antibodies were also found both in the mouse models and in CD patients further confirming the involvement of the adaptive immune response. Whether abberant TLR5 activity or a T cell defect causes the hyperactive response to flagellin is not yet known. TLR activity is subject to a variety of tight controls. One mechanism to regulate TLR activity is illustrated by the inhibitory TLR called TIR8, which acts as an intracellular decoy of signaling molecules required for TLR function. TIR8 traps intracellular proteins called TRAF6 and IRAK1, which various TLRs use to signal to the NF-kB pathway. Mice genetically deficient in TIR8 therefore lack this normal regulation of TLR function, and these mice were shown to have increased susceptibility to intestinal inflammation following treatment with a chemical known to damage the gut epithelium (C. Garlanda et al., PNAS 101, 3522 (2004). Of interest, TIR8 was expressed both in the mucosal epithelial cells themselves, but also in dendritic cells, which are critical mediators of the activation of T cells. Therefore, TIR8 appears likely to play a role in modulating both innate and acquired immune responses to TLR signals. As mentioned above, TLRs must recognize and respond to the massive numbers of commensal bacteria in the gut, as well as pathogens. One function TLR pathways have evolved is to protect cells in the presence of commensal bacteria should injury to the gut wall occur. This was shown is a series of studies using mice deficent in various TLRs, or the TLR-signaling molecule MyD88 (S. Rakoff-Nahoum et al., Cell 188, 229 (2004). Since MyD88 transduces TLR signals to the NF-kB pathway, this is consistent with the observation that TLRs mediate protection through induction of cell survival signals, and expression of protective cytokines and other factors. Indeed another recent study showed the blockade of NF-kB signaling in the gut epithelium caused increased damage following local injury (L.W. Chen et al., Nat Med 9, 575 (2003). Such data point out the delicate balance that must be maintained for TLR and other signals to NF-kB: too much activation causes inflammation and disease; too little leaves the gut wall susceptible to injury and infection. Some strains of bacteria have even evolved means to dampen NF-kB signaling directly as a means to disrupt this delicate balance and allow infection to occur (A. S. Neish et al., Science 289, 1560 (2000), D. Kelly et al. Nat Immunol 5, 104 (2004). Finally, the importance of NF-kB-driven chronic inflammation in the gut extends beyond IBD. It is very clear that IBD, particularly UC, is an important risk factor for the development of colorectal cancer. NF-kB signaling is suspected to play a role in many cancer types, and the utility of targeting this pathway in cancer has been demonstrated by the drug Velcade, which functions in part by preventing NF-kB activation (P. M. Voorhees et al., Clin Can Res 9, 6316 (2003). The role of NF-kB in the development of intestinal cancers in mouse has recently begun to be elucidated (H. Clevers, Cell 118, 671 (2004), suggesting that further study of the role of innate immunity and NF-kB signaling in gut inflammation may shed light not only of the pathogenesis of IBD, but of gut tumorigenesis as well. ### Paul D. Rennert Department of Immunology, Biogen Idec, Inc. 12 Cambridge Ctr, Cambridge, MA 02142 A Member of The Science Advisory Board Steering Commmittee ### << Previous Next >> [ View All Perspectives ] |
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