NOD2 and inflammation: current insights

Abstract

The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene.

Keywords: ER stress; autophagy; extraintestinal disease; inflammatory bowel disease; innate immunity; intestinal homeostasis.

Figure 1

Structure of the NLR subfamilies. Abbreviations: AD, atopic dermatitis; BIR, baculovirus inhibitor repeat; CARD, caspase recruitment domain; CIITA, class II major histocompatibility complex transactivator; FIIND, function to find domain; LRR, leucine-rich repeat; NAD, NBD-associated domain; NBD, nucleotide-binding domain; NLR, NOD-like receptor; NLRA, acidic transactivation domain; NLRB, baculovirus inhibitor repeat; NLRC, caspase recruitment domain; NLRP, NLR family pyrin domain; NOD, nucleotide-binding oligomerization domain; PYD, pyrin domain; X, unknown effector domain.

Figure 2

Signaling pathways triggered by NOD2. Abbreviations: AP-1, activator protein-1; ATF6, activating transcription factor 6; ATG, autophagy-related genes; ATG16L1, autophagy related 16 like 1; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IFNs, interferons; IKB, NF-κB inhibitor; IKK, IκB kinase; IRF3, interferon response factor 3; JNK, c-Jun N-terminal kinase; MAVS, mitochondrial antiviral signaling; MDP, muramyl dipeptide; NEMO, NF-κB essential modulator; NOD, nucleotide-binding oligomerization domain; PERK, protein kinase RNA-like endoplasmic reticulum kinase; RIP2, receptor-interacting protein kinase 2; TAB, TGF-β activated kinase; TAK1, targets transforming growth factor-β-activated kinase 1; UPR, unfolded protein response.