Sensor molecules in intestinal innate immunity against bacterial infections

Abstract

Purpose of review: Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-containing proteins are innate immune sensors for microbial signature molecules. This review highlights new insights into the functions of these sensors in intestinal physiology.

Recent findings: TLRs are membrane bound and survey the extracellular space for microbe-derived molecules, while NOD-containing proteins are cytoplasmic and detect microbial molecules in the cytoplasm. Most microbial sensors recognize components of the bacterial cell wall and its appendages. For example, TLR4 detects lipopolysaccharide in the Gram-negative bacterial cell wall. TLR5 recognizes flagellin, a component of bacterial flagella required for motility. NOD1 recognizes diaminopimelic acid-containing dipeptide or tripeptide motifs in the Gram-positive bacterial cell wall, while NOD2 detects muramyl dipeptide, a ubiquitous cell wall peptidoglycan motif. These sensors are important for host defense against gastrointestinal pathogens. Thus, TLR4 is required for Salmonella eradication, NOD1 contributes to controlling Helicobacter pylori infection, and NOD2 is involved in mucosal defense against Listeria monocytogenes. These sensors also regulate mucosal inflammation independent of pathogen infections.

Summary: Toll-like receptors and nucleotide-binding oligomerization domain-containing proteins not only play critical roles in host defense against known gastrointestinal bacterial pathogens, but also contribute to mucosal homeostasis in the apparent absence of such pathogens.

Figure 1. Caspase recruitment domain (CARD)-containing intracellular sensor and adaptor proteins

The scheme depicts the different CARD-containing adaptors and sensors discussed in the review. CARD6/CARD7/CARD10/CARD14 and other CARD-containing molecules (e.g. caspases, APAF1, CIITA, Arc, RAIDD, ICEBERG) are not included here, as little is known about their intestinal functions. iEDAP, γ-D-glutamyl-meso-diaminopimelic acid; MAPK, mitogen-activated protein kinases; MDP, muramyl dipeptide; NF, nuclear factor.

Figure 2. CARD9 functions in myeloid cells

After activation of membrane-bound microbial sensors such as Toll-like receptors (TLRs) and immunoreceptor tyrosine-based activation motif (ITAM)-containing non-TLRs, and the cytoplasmic sensor NOD2 (CARD15), signaling pathways converge on CARD9. Stimulation of dectin-1 with the fungus-derived ligand zymosan or of TREM-1 (unknown specific ligand) induces phosphorylation of specific tyrosine residues in the ITAMs, leading to downstream formation of a signaling complex of CARD9 with other adaptor proteins, particularly BCL10 and MALT1. TLRs can activate RIP2 (CARD3) and CARD9 in response to a broad range of microbial ligands, while NOD2 interacts with RIP2 and CARD9 via CARD–CARD interactions upon intracellular recognition of muramyl dipeptide. Formation of the signaling complex with CARD9, BCL-10 and MALT1 leads to activation of nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPK), and subsequently secretion of proin-flammatory cytokines. TLRs can also activate NF-κB through a CARD9-independent pathway.