ROLE OF PATTERN RECOGNITION RECEPTORS IN MODULATING INTESTINAL IMMUNE RESPONSES AND POTENTIAL THERAPEUTIC IMPLICATIONS FOR INFLAMMATORY BOWEL DISEASES

The intestinal mucosal barrier must exert a highly defined process of discrimination, excluding potential pathogens while allowing host-beneficial substances (e.g., nutrients) to permeate. Imbalance within this complex network of cell and microbial interactions appears to play a key role in the pathogenesis of inflammatory bowel diseases (IBD) and other gastrointestinal disorders. Toll-like receptors (TLRs) comprise a class of transmembrane pattern recognition receptors (PRRs) which play a key role in microbial recognition, the induction of antimicrobial responses, and the control of adaptive immune responses. TLRs and CARD4 and CARD15 are widely expressed by various cell types of the gastrointestinal mucosa. Recent studies have greatly advanced the understanding of the mechanisms through which the gastrointestinal innate immune system mediates the recognition and sorting of the broad luminal spectrum of microbial products. These studies have also suggested that alteration in mammalian TLR and CARD expression and function plays key roles in the pathophysiology of IBD, opening a multitude of anti-inflammatory therapeutic opportunities which are discussed in this chapter. The authors recently found that trypsin, which is abundantly secreted in intestinal inflammation, leads to the proteolysis of MD-2, an essential coreceptor of TLR4 required for optimal LPS recognition and signaling. It is likely that TLR pathways need to be differentially exploited by fine-tuned combinations of distinct TLRx agonists in conjunction with specific TLRy antagonists at different stages of disease in order to induce salutary immune responses in acute versus chronic IBD.