Chapter 5 : Role of Toll-Like Receptors in Innate Immunity of the Intestine

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The pre-epithelial mucous layer at the apical epithelial surface-consisting of mucin glycoproteins, trefoil peptides, and, in the small intestine, defensins-significantly contributes to efficient protection of the underlying host. Toll-like receptors (TLR) are found expressed by many cell types throughout the whole gastrointestinal tract in vitro and in vivo, e.g., several intestinal epithelial cells (IEC) lines of the small intestine and colon, gastric pit cells, fetal intestinal cells, intestinal macrophages of the lamina propria, and intestinal myofibroblasts. Mammalian TLR may enable IEC to participate in innate immunity to microbial pathogens in at least four ways: (i) recognition of molecular patterns present on commensals and pathogens; (ii) expression at the interface with the “environment” of the gastrointestinal lumen; (iii) induction of secretion of pro-or anti-inflammatory cytokines and chemokines that link to the adaptive immune system; and (iv) induction of antimicrobial effector pathways. The chapter talks about alteration of TLR expression in human inflammatory bowel disease (IBD), and TLR dysregulation in infectious diseases. Future research will identify further TLR ligands, specify interconnective signaling cascades activated by TLR, and clarify the potential role of intestinal epithelial TLR in the pathogenesis of IBD and other aberrant inflammatory processes in the gastrointestinal tract. Identifying the physiological mechanisms through which intestinal TLR and other pattern-recognition receptors (PRR) modulate host defense in the gastrointestinal tract could lead to new therapeutic approaches to combat microbial associated gastrointestinal disorders, such as infectious diseases and perhaps IBD.

Citation: Cario E, Podolsky D. 2003. Role of Toll-Like Receptors in Innate Immunity of the Intestine, p 79-94. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch5

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Different PAMPs activate different TLRs. TLRs recognize specifically a restricted number of PAMP or CAMP. TLR2 interacts with TLR1 and TLR6 in recognition of a variety of ligands, mainly gram-positive bacterial cell wall components. Aided by at least three other molecules, including CD14, LPS-binding-protein (LBP), and MD-2, TLR4 mainly detects LPS. Double-stranded RNA is recognized by TLR3, and TLR5 binds flagellin. TLR9 is a receptor for abundant bacterial CpG DNA. The ligands for TLR7, TLR8, and TLR10 remain to be determined.

Citation: Cario E, Podolsky D. 2003. Role of Toll-Like Receptors in Innate Immunity of the Intestine, p 79-94. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch5
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Image of FIGURE 2.

Signaling pathways of TLRx—current concept. TLR signal through several signaling components, including the adapter protein MyD88, Toll-interacting protein (Tollip), IL-1R-associated kinase (IRAK), and TNF receptor-associated factor 6 (TRAF-6), leading to liberation of the transcription factor NF-ĸB and activation of MKK and the JNK-p38 pathways. All these events lead downstream to the transcription of various cytokine/chemokine genes. TLR4 also signals through an MyD88-independent pathway via another adapter, recently identified as TIRAP (or Mal). The interactions among TLR versus MyD88, TIRAP, and Tollip are complex and remain unresolved. The protein kinase PKR is possibly positioned between TIRAP and TRAF-6. Rho GTPase Rac-1 and Akt have also been shown to mediate TLR2-dependent activation. The roles of other PRR, such as TREM or Nods, possibly interacting with TLR signaling proteins and thus regulating innate immune responses to bacterial ligands, remain to be defined.

Citation: Cario E, Podolsky D. 2003. Role of Toll-Like Receptors in Innate Immunity of the Intestine, p 79-94. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch5
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