Role of Toll-like receptors in health and diseases of gastrointestinal tract

Abstract

The human gastrointestinal (GI) tract is colonized by non-pathogenic commensal microflora and frequently exposed to many pathogenic organisms. For the maintenance of GI homeostasis, the host must discriminate between pathogenic and non-pathogenic organisms and initiate effective and appropriate immune and inflammatory responses. Mammalian toll-like receptors (TLRs) are members of the pattern-recognition receptor (PRR) family that plays a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. This review summarizes the current understanding of the crucial dual roles of TLRs in the development of host innate and adaptive immune responses to GI infections and the maintenance of the immune tolerance to commensal bacteria through down-regulation of surface expression of TLRs in intestinal epithelial cells.

Figure 1

Host sensing of enteropathogenic bacteria. Enteroinvasive bacteria are sensed by specific cells (intestinal epithelial cells, M cells, macrophages and dendritic cells) located in the intestinal mucosa. Resident and invasive bacteria and their molecules released into the intestinal lumen could be recognized by host cells. Sensing of bacteria and their products are mediated by surface Toll-like receptors (TLRs) and cytosolic Nod1 receptors. Intestinal epithelial cells lack functional TLR2 and TLR4 but they might express TLR5 at the basolateral surface. Thus, some entero-invasive flagellate bacteria might stimulate epithelial cells through both TLR5 and Nod1 (depicted in red), whereas other invasive bacteria might activate Nod1 but not TLRs (depicted in green). Flagellate Gram-positive bacteria lacking Nod1-stimulating molecules are expected to trigger TLRs but not Nod1 signaling (depicted in blue). Soluble TLR- and Nod1-stimulating products are found in the intestinal contents but their role in host defense is unknown. Certain TLRs might be also localized to intracellular compartments (e.g., Golgi apparatus for TLR4), but the relevance of intracellular TLR signaling in the intestinal mucosa remains elusive. Reprinted from Chamaillard et al. Battling enteroinvasive bacteria: Nod1 comes to the rescue.Trends Microbiol 12:529-532[154]. Copyright (2004), with permission from Elsevier.