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NOD2 and Inflammation: Current Insights Journal name: Journal of Inflammation Research Article Designation: REVIEW Year: 2018 Volume: 11 Journal of Inflammation Research Dovepress Running head verso: Negroni et al Running head recto: NOD2 and inflammation open access to scientific and medical research DOI: http://dx.doi.org/10.2147/JIR.S137606 Open Access Full Text Article REVIEW NOD2 and inflammation: current insights Anna Negroni1 Abstract: The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to Maria Pierdomenico2 the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan Salvatore Cucchiara2 and promotes their clearance through activation of a proinflammatory transcriptional program Laura Stronati3 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 1Division of Health Protection Technologies, Territorial and with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for Production Systems Sustainability the maintenance of immune homeostasis. In this review, we discuss recent developments about Department, ENEA, Rome, Italy; the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of 2Department of Pediatrics and Infantile Neuropsychiatry, Pediatric the gene, with particular emphasis on its central role in maintaining the equilibrium between Gastroenterology and Liver Unit, intestinal microbiota and host immune responses to control inflammation. Furthermore, we sur- For personal use only. Sapienza University of Rome, Rome, vey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, Italy; 3Department of Cellular Biotechnology and Hematology, inflammatory bowel disease, of which it is the main susceptibility gene. Sapienza University of Rome, Rome, Keywords: innate immunity, intestinal homeostasis, ER stress, autophagy, inflammatory bowel Italy disease, extraintestinal disease Introduction The human body is constantly in contact with a myriad of microorganisms, either pathogens or commensals. Innate immune system, which provides a first line of defense against many common microbes, is essential for an appropriate tissue homoeostasis as well as for common bacterial infections, and its dysfunction leads to infectious, inflammatory and autoimmune diseases. Journal of Inflammation Research downloaded from https://www.dovepress.com/ by 137.108.70.14 on 15-Jan-2020 Innate immune response relies on recognition of evolutionarily conserved structures on the microorganisms, termed pathogen-associated molecular patterns (PAMPs), through a limited number of germ line-encoded pattern recognition receptors (PRRs) present on the host cell surface or in the intracellular compartments.1 Among the lat- ter, nucleotide-binding and oligomerization domain containing protein 2 (NOD2) is a cytosolic receptor belonging to the nucleotide-binding oligomerization (NOD)-like receptor (NLR) family.2 NOD2 is able to detect intracellular muramyl dipeptide (MDP), a component of the bacterial wall that is ubiquitously present in bacterial peptidogly- can.3 Upon activation by ligand, NOD2 mediates innate immune response triggering Correspondence: Laura Stronati proinflammatory responses. NOD2 mutation or altered expression has been found Department of Cellular Biotechnology and Hematology, Sapienza University in patients with chronic inflammatory disorders such as Crohn’s disease (CD), Blau of Roma, Viale Regina Elena 324, 00161 syndrome (BS) and early-onset sarcoidosis (EOS).4–9 In this review, we summarize the Rome, Italy current knowledge about NOD2 functions and regulation, as well as its involvement Tel +39 064 997 4393 Email [email protected] in chronic inflammatory diseases. submit your manuscript | www.dovepress.com Journal of Inflammation Research 2018:11 49–60 49 Dovepress © 2018 Negroni et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/JIR.S137606 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Negroni et al Dovepress The NLR family NOD2 signaling The 23 NLR family members, intracellular sensors of The innate immune system is critical for clearing infection PAMPs, share a common organization consisting of a and averting excessive tissue damage. NOD2, an intracellular C-terminal leucine-rich repeat (LRR) domain with regulatory receptor of microbial components derived from bacterial and ligand recognition functions, a central nucleotide-binding peptidoglycan, contributes to the maintenance of mucosal and oligomerization domain (NBD) and an N-terminal homeostasis and the induction of mucosal inflammation. effector-binding domain. The type of effector domain results Structurally, NOD2 protein is composed of two tandem in the division of NLR proteins into five subfamilies: acidic N-terminal CARDs that function as effector domain and transactivation domain (NLRA); baculovirus inhibitor repeat, mediate specific homophilic interaction with downstream BIR (NLRB); caspase recruitment domain, CARD (NLRC); CARD-containing molecules.16 On activation by MDP, a cell pyrin domain (NLRP) and NLRX1 that localizes to the wall component of both Gram-positive and Gram-negative mitochondria and has no homology to any known N-terminal bacteria, through LRR domain, NOD2 undergoes self- domain (Figure 1).10,11 NOD2 belongs to the NLRC subfamily oligomerization and recruitment of the downstream adaptor of NLRs and, after NOD1, has been the second member of molecule, the kinase receptor interacting protein 2 (RIP2 the family to be identified.12 NOD2 receptor, encoded by the also known as RICK, CARDIAK, CCK and Ripk2), via NOD2/CARD15 gene, mapping on chromosome 16q12.1 in homophilic CARD–CARD interaction.17–19 Active RIP2 leads humans, consists of 1040 amino acids and has a molecular to ubiquitination of nuclear factor-kappa B (NF-κB) essen- weight of 110 kDa.12 It is expressed in monocytes, macro- tial modulator, resulting in activation of IκB kinase (IKK) phages, dendritic cells, hepatocytes, preadipocytes, epithelial complex that phosphorylates NF-κB inhibitor-α (IKBα), the cells of oral cavity, lung and intestine, with higher expression inhibitor of transcription factor NF-κB, which translocates to in ileal Paneth cells and in intestinal stem cells.13,14 NOD2, the nucleus and starts transcription of proinflammatory genes, like NOD1, is a cytoplasmic protein, although it is recruited including cytokines, growth factors and factors responsible 20,21 For personal use only. in the plasmatic membrane where it detects bacterial invasion for stimulation of immune cells. RIP2 targets transform- at the point of entry.15 ing growth factor-β-activated kinase 1, which, through IKK PYD NBDNAD LRR FIIND CARD NLRP1 NLRP subfamily PYD NBD NAD LRR NLRP2–9/NLRP11–14 PYD NBD NAD NLRP10 CARD NBD NAD LRR NOD1/NLRC3–5 NLRC subfamily NOD2 Journal of Inflammation Research downloaded from https://www.dovepress.com/ by 137.108.70.14 on 15-Jan-2020 CARD CARD NBD NAD LRR NLRA subfamily CARD AD NBD NAD LRR CIITA BIRBIR BIR NBD LRR NAIP NLRB subfamily X NBD NAD LRR NLRX1 NLRX subfamily 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. 50 submit your manuscript | www.dovepress.com Journal of Inflammation Research 2018:11 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress NOD2 and inflammation complex, activates MAP kinases and transcription factor Acti- Migratory Cell Protein, Carbamoyl-Phosphate Synthe- vator Protein 1 involved in cell proliferation, differentiation tase 2, Mitogen-Activated Protein Kinase Binding Protein 1 and apoptosis.18,22 NOD2 is also known to bind and activate (JNKBP1) and heat shock protein (HSP) 90 have been shown caspase-1, through its CARD domain, and starts interleukin to interact with NOD2 and regulate downstream signaling (IL)-1β processing.23 Moreover, MDP challenge promotes the events.26–30 Recently, Suppressor of Cytokine Signaling-3 was formation of NOD2–NLR family pyrin domain containing 1 found to recruit the ubiquitin machinery to NOD2, facilitating complex that induces caspase-1–dependent IL-1β secretion in its proteasomal degradation.30 Interferon regulatory factor 4 response to Bacillus anthracis or Yersinia pseudotuberculosis (IRF4) is another negative regulator of NOD2-dependent infection.23,24 Recently, NOD2 has been suggested to have a NF-κB signaling through inhibition
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