NOD2 and inflammation: current insights

Journal of Inflammation Research, Feb 2018

NOD2 and inflammation: current insights Anna Negroni,1 Maria Pierdomenico,2 Salvatore Cucchiara,2 Laura Stronati3 1Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy; 2Department of Pediatrics and Infantile Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy; 3Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy 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: innate immunity, intestinal homeostasis, ER stress, autophagy, inflammatory bowel disease, extraintestinal disease

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NOD2 and inflammation: current insights

Journal of Inflammation Research NOD2 and inflammation: current insights Anna Negroni 2 Maria Pierdomenico 1 Salvatore Cucchiara 1 Laura Stronati 0 0 Department of Cellular Biotechnology and Hematology, Sapienza University of Rome , Rome , Italy 1 Department of Pediatrics and Infantile Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome , Rome , Italy 2 Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA , Rome , Italy 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. innate immunity; intestinal homeostasis; ER stress; autophagy; inflammatory bowel - ed F d a o l n w o d h c r a e s e R n o it a m m a lf n I f o l a n r u o J open access to scientific and medical research 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. 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 latter, 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 peptidoglycan.3 Upon activation by ligand, NOD2 mediates innate immune response triggering proinflammatory responses. NOD2 mutation or altered expression has been found in patients with chronic inflammatory disorders such as Crohn’s disease (CD), Blau syndrome (BS) and early-onset sarcoidosis (EOS).4–9 In this review, we summarize the current knowledge about NOD2 functions and regulation, as well as its involvement in chronic inflammatory diseases. The NLR family The 23 NLR family members, intracellular sensors of PAMPs, share a common organization consisting of a C-terminal leucine-rich repeat (LRR) domain with regulatory and ligand recognition functions, a central nucleotide-binding and oligomerization domain (NBD) and an N-terminal effector-binding domain. The type of effector domain results 2801 in the division of NLR proteins into five subfamilies: acidic l--Ju transactivation domain (NLRA); baculovirus inhibitor repeat, 12 BIR (NLRB); caspase recruitment domain, CARD (NLRC); n 7o pyrin domain (NLRP) and NLRX1 that localizes to the .206 mitochondria and has no homology to any known N-terminal .495 domain (Figure 1).10,11 NOD2 belongs to the NLRC subfamily . 73 of NLRs and, after NOD1, has been the second member of /yb the family to be identified.12 NOD2 receptor, encoded by the .com NOD2/CARD15 gene, mapping on chromosome 16q12.1 in rsse humans, consists of 1040 amino acids and has a molecular p weight of 110 kDa.12 It is expressed in monocytes, macro.vdoew l.yno phages, dendritic cells, hepatocytes, preadipocytes, epithelial /ww seu cells of oral cavity, lung and intestine, with higher expression :/ l ttsp ona in ileal Paneth cells and in intestinal stem cells.13,14 NOD2, h rs froedm rpeoF liniktehNepOlaDs1m,aistica mcyetmopblraasnmeiwchperroeteitind,eateltchtosubgahctietriisalriencvrausiitoend at the point of entry.15 d a o l n w o d h c r a e s e R n o it a m m a lf n I f o l a n r u o J NBD NBD NBD NBD NBD NAD NAD NAD NAD NAD CARD CARD AD NBD NAD BIR BIR NBD PYD PYD PYD CARD CARD BIR X LRR LRR LRR LRR LRR LRR LRR NOD2 signaling The innate immune system is critical for clearing infection (...truncated)


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Anna Negroni, Maria Pierdomenico, Salvatore Cucchiara, Laura Stronati. NOD2 and inflammation: current insights, Journal of Inflammation Research, 2018, pp. 49-60, DOI: 10.2147/JIR.S137606