NOD-like receptors (NLRs) are a family of more than 20 different cytosolic proteins, some of which recognize PAMPs and DAMPs and recruit other proteins to form signaling complexes that promote inflammation (Table 1). Typical NLRs contain a C-terminal leucine-rich repeat domain that senses the presence of ligand; a central NOD (nucleotide oligomerization domain, also called NACHT) domain required for NLR proteins to bind to one another and form oligomers; and an N-terminal effector domain, which recruits other proteins to form signaling complexes. Three NLR subfamilies serve as innate immune receptors, each using a different effector domain to initiate signaling. These include NLRB, which uses the BIR (baculovirus inhibition of apoptosis protein repeat) effector domain; NLRC, which uses CARDs (caspase recruitment and activation domains); and NLRP, which uses pyrin domains (so-called because they are found in proteins involved in causing fever) (see Table1). NLRs are found in a wide variety of cell types, although some have restricted cellular expression. Some of the best studied NLRs are found in immune and inflammatory cells and in barrier epithelial cells. We will discuss two NLR sensors of bacterial PAMPs here, named NOD1 and NOD2, and other NLRs later, when we discuss inflammasomes.
Table1. NOD-Like Receptors
NOD1 and NOD2, members of the NLRC subfamily, are expressed in the cytosol of several cell types, including mucosal epithelial cells and phagocytes, and they respond to bacterial cell wall peptidoglycans. NOD2 is highly expressed in intestinal Paneth cells in the small bowel, where it stimulates expression of antimicrobial cationic peptides called defensins in response to pathogens. Both NOD1 and NOD2 recognize components of bacterial cell walls. NOD1 recognizes a glycosylated tripeptide called diaminopimelic acid (DAP), derived mainly from gram negative bacterial peptidoglycan, whereas NOD2 recognizes a distinct molecule called muramyl dipeptide (MDP), derived from peptidoglycans of both gram-negative and gram-positive bacteria. These peptides are released from intracellular or extra cellular bacteria; in the latter case, their presence in the cytosol requires specialized bacterial mechanisms of delivery of the peptides into host cells. These mechanisms include type III and type IV secretion systems, which have evolved in pathogenic bacteria as a means of delivering toxins into host cells. NOD1 and NOD2 can also be activated by other microbial PAMPs, including bacterial proteins and viral RNAs. When oligomers of NODs recognize their ligands, a conformational change occurs that allows the CARD effector domains of the NOD proteins to recruit many molecules of the kinase RIP2, forming a signaling complex that has been called the NOD signalosome. The RIP2 kinases in these complexes activate NF-κB, which stimulates production of cytokines and other molecules involved in inflammation, similar to TLRs that signal through MyD88, discussed earlier. Both NOD1 and NOD2 appear to be important in innate immune responses to bacterial pathogens in the gastrointestinal tract, such as Helicobacter pylori and Listeria monocytogenes.
Certain NOD2 gene polymorphisms increase the risk for an inflammatory disease of the bowel called Crohn’s disease. A possible explanation for this association is that the disease associated NOD2 variants are defective in their ability to sense microbial products, resulting in defective innate responses against commensal and pathogenic organisms in the intestine. If these organisms gain access to the intestinal wall, they may trigger chronic inflammation. Also, gain-of-function mutations of NOD2 that cause increased NOD signaling and NF-κB activation lead to a systemic inflammatory disease called Blau syndrome.
