NOD-Like Receptors in Infection, Immunity, and Diseases

Abstract

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives.

Keywords: Innate immunity; NOD-like receptors; inflammasomes; pattern recognition receptors.

Fig. 1. Classification and protein structure of human NOD-like receptor family (based on Ref. 6). AD, acidic transactivation domain; NACHT, for NAIP, CIITA, HET-T, and TP-1; BIR, baculovirus inhibitor of apoptosis repeat; CARD, caspase activation and recruitment domain; X, unidentified; PYD, pyrin domain, FIIND, function to find domain; , leucine-rich repeat; NOD, nucleotide-binding and oligomerization domain.

Fig. 2. Functions of NOD-like receptors. The NLRs activities can be divided into four broad categories; autophagy, signal transduction, transcription activation, and inflammasome formation. NOD2 induces autophagy to remove pathogens by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. NOD1 and NOD2 recognize γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP) respectively; thereafter they activate the NF-κB and MAPK signaling pathways. NLRP2 and NLRP4 act as negative regulators of NF-κB pathway by modifying TRAF6. CIITA and NLRC5 are transactivators of major histocompatibility complexes (MHC). Inflammasome-forming NLRs (orange circle) convert procytokines to active IL-1β and IL-18 by activating caspase-1. NOD, nucleotide-binding and oligomerization domain; NLRs, NOD-like receptors; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; TRAF, tumor necrosis factor (TNF) receptor-associated factor; IL, interleukin; INF-γ, interferon-γ.