TLRs in the Gut I. The role of TLRs/Nods in intestinal development and homeostasis

Abstract

The innate immune system includes microbial pattern recognition receptors that detect bacteria and viral products at the cell surface, in vesicles, and within the cytoplasm. Transmembrane signaling occurs through Toll-like receptors (TLRs). Cytoplasmic receptors are generally members of the nucleotide-binding domain (NOD)-leucine-rich repeat (LRR) family (CATERPILLER family). They influence the effects of other family members and of TLRs. Most NOD-LRR members enhance signal transduction, but Monarch-1 counterbalances TLR activity. NOD-LRR family members also act within the adaptive immune system. The class II transactivator regulates major histocompatibility complex class II expression. In the intestine, it is developmentally regulated, and its expression depends on weaning and, independently, on age.

Fig. 1

Pattern recognition receptors recognize microbial products on the eukaryotic cell exterior, within vesicles, and in the cytoplasm. In general, Toll-like receptor (TLR)1, TLR2, TLR4, TLR5, and TLR6 act from the cell surface to detect peptide- and carbohydrate-based structures from bacteria. Microbial nucleic acid is internalized into vesicles and recognized by TLR3, TLR7, TLR8, and TLR9. Nucleotide-binding domain (NOD)-leucine-rich repeat (LRR) family (CATERPILLER family) members recognize microbial products in the cytoplasm. Each receptor, when ligated, stimulates one or more signal transduction pathways like NF-κB and JNK (but includes a wide range of processes including interferon regulatory factor). TIR, Toll-IL-1 receptor; CARD, caspase recruitment domain; CIITA, class II transactivator; IPAF, IL-1β-converting enzyme-protease-activating factor; PYD, pyrin domain; AD, activation domain.

Fig. 2

Nod1 and Nod2 recognize two closely related subunits of bacterial peptidoglycan. The Nod1 ligand γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) is found in gram-negative bacteria and in some gram-positive bacteria. When this includes the D-alanine residue from the peptidoglycan, the ligand is termed TriDAP. Neither the double residue (iE-DAP) of the triple residue (TriDAP) is part of the peptidogly-can backbone, which consists of alternating N-acetyl-glucosamine (GlcNAc)/N-acetyl-muramic acid residues (MurNAc). Nod2, however, recognizes MurNAc when linked to its adjacent side chain residues, muramyl dipeptide (MDP), which is present in both gram-positive and gram-negative bacteria. Regulation of the mechanisms that hydrolyze the cell wall and process the residues for Nod1 and Nod2 recognition is an area of active investigation. mDAP, meso-diaminopimelic acid.