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Nucleotide-binding oligomerization domain containing 1 (NOD1) and NOD2 are pivotal cytoplasmic pattern-recognition receptors (PRRs) that exhibit remarkable evolutionary conservation. They possess the ability to discern specific peptidoglycan (PGN) motifs, thereby orchestrating innate immunity and contributing significantly to immune homeostasis maintenance. The comprehensive understanding of both the structure and function of NOD1 and NOD2 has been extensively elucidated. These receptors proficiently recognize an array of damage-associated molecular patterns (DAMPs) as well as pathogen-associated molecular patterns (PAMPs), subsequently mediating inflammatory responses and autophagy. In recent years, emerging evidence has highlighted the crucial roles played by NOD1 and NOD2 in regulating infectious diseases, metabolic disorders, cancer, and autoimmune conditions, among others. Perturbation in either their loss or excessive activation can detrimentally impact immune homeostasis. This review offers a comprehensive overview of the structural characteristics, subcellular localization, activation mechanisms, and significant roles of NOD1 and NOD2 in innate immunity and related disease.

NOD1 and NOD2 as two representative members of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family play important roles in antimicrobial immunity. However, transcription mechanism of nod1 and nod2 and their signal circle are less understood in teleost fish. In this study, with the cloning of card9 and ripk2 in Chinese perch, the interaction between NOD1, NOD2, and CARD9 and RIPK2 were revealed through coimmunoprecipitation and immunofluorescence assays. The overexpression of NOD1, NOD2, RIPK2 and CARD9 induced significantly the promoter activity of NF-kB, IFNh and IFNc. Furthermore, it was found that nod1 and nod2 were induced by poly(I:C), type I IFNs, RLR and even NOD1/NOD2 themselves through the ISRE site of their proximal promoters. It is thus indicated that nod1 and nod2 can be classified also as ISGs due to the presence of ISRE in their proximal promoter, and their expression can be mechanistically controlled through PRR pathway as well as through IFN signaling in antiviral immune response. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain-like receptors (NOD-like receptors) are cytosolic signaling receptors of innate immune cells recognizing ligands derived from bacteria, viruses, fungi and protozoa. They can initiate apoptosis and pro-inflammatory cytokines production. Meanwhile, the role of decidual NOD-like receptors in pathogenesis of early miscarriages remains unknown. Aim: to study NOD-like receptor (NOD1, NOD2, NLRP1, NLRP3, NLRC4) messenger ribonucleic acid (mRNA) expression in decidual tissue from patients with missedand spontaneous abortions compared to progressive pregnancy.Materials and Methods. NOD1, NOD2, NLRP1, NLRP3, NLRC4 and pathway protein receptorinteracting-serine/threonine-protein kinase 2 (RIP-2) mRNA expression in decidua from 34 patients with missed abortions (group I), 34 patients with spontaneous abortions (group II) and 57 women with progressive pregnancy admitted for artificial abortion (group III, control group) were analyzed by reverse transcription quantitative polymerase chain reaction (PCR) at gestational age of 6–10 weeks. Exclusion criteria were as follows: endocrine disorders, severe extragenital diseases, antiphospholipid syndrome, inherited thrombophilia, uterine malformations and fetal chromosomal abnormalities. Samples were collected by uterine abrasion. Results. It was found that mRNA expression of NOD2 was significantly higher in decidua from patients with missed and spontaneous abortions, whereas for RIP-2 (related to relevant signaling pathway) – in women with missed abortions. A moderate positive correlation between gestational age and mRNA expression for NOD2 (R = 0.48; p = 0.01) and RIP-2 (R = 0.41; p = 0.007) was observed in subjects with progressive pregnancy. In contrast, women with missed abortions showed a moderate negative correlation between body weight and mRNA expression for NOD2 (R = –0.46; p = 0.03) and RIP-2 (R = –0.51; p = 0.02) whereas spontaneous abortions was associated with moderate negative correlation between RIP-2 mRNA expression and body weight (R= –0.47; p=0.04) as well as body mass index (R= –0.48; p = 0.04) along with moderate positive correlation with age of menarche (R = 0.46; p = 0.04). However, compared with progressive pregnancy no significant differences were found in expression level form NOD1, NLRP1, NLRP3 and NLRC4 mRNA in decidua from patients with missed and spontaneous abortions. Conclusion. Elevated NOD2 mRNA expression was observed in decidua from patients with missed and spontaneous abortions compared to progressive pregnancy paralleled with upregulated RIP-2 mRNA expression in missed abortions. Finally, it was found that NOD1, NLRP1, NLRP3 and NLRC4 were not involved in pathogenesis of miscarriages.

Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.

Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases. [ABSTRACT FROM AUTHOR]

Hepatocytes and liver-resident antigen-presenting cells are exposed to microbe-associated molecular patterns (MAMPs) and microbial metabolites, which reach the liver from the gut via the portal vein. MAMPs induce innate immune responses via the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), nucleotide-binding oligomerization domain 1 (NOD1), and NOD2. Such proinflammatory cytokine responses mediated by PRRs likely contribute to the development of chronic liver diseases and hepatocellular carcinoma (HCC), as shown by the fact that activation of TLRs and subsequent production of IL-6 and TNF-a is required for the generation of chronic fibroinflammatory responses and hepatocarcinogenesis. Similar to TLRs, NOD1 and NOD2 recognize MAMPs derived from the intestinal bacteria. The association between the activation of NOD1/NOD2 and chronic liver diseases is poorly understood. Given that NOD1 and NOD2 can regulate proinflammatory cytokine responses mediated by TLRs both positively and negatively, it is likely that sensing of MAMPs by NOD1 and NOD2 affects the development of chronic liver diseases, including HCC. Indeed, recent studies have highlighted the importance of NOD1 and NOD2 activation in chronic liver disorders. Here, we summarize the roles of NOD1 and NOD2 in hepatocarcinogenesis and liver injury. [ABSTRACT FROM AUTHOR]

Asthma is an extremely prevalent chronic inflammatory disease of the airway where innate and adaptive immune systems participate collectively with epithelial and other structural cells to cause airway hyperresponsiveness, mucus overproduction, airway narrowing, and remodeling. The nucleotidebinding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular innate immune sensors that detect microbe-associated molecular patterns and damage-associated molecular patterns, well-recognized for their central roles in the maintenance of tissue homeostasis and host defense against bacteria, viruses and fungi. In recent times, NLRs have been increasingly acknowledged as much more than innate sensors and have emerged also as relevant players in diseases classically defined by their adaptive immune responses such as asthma. In this review article, we discuss the current knowledge and recent developments about NLR expression, activation and function in relation to asthma and examine the potential interventions in NLR signaling as asthma immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

Asthma is an extremely prevalent chronic inflammatory disease of the airway where innate and adaptive immune systems participate collectively with epithelial and other structural cells to cause airway hyperresponsiveness, mucus overproduction, airway narrowing, and remodeling. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular innate immune sensors that detect microbe-associated molecular patterns and damage-associated molecular patterns, well-recognized for their central roles in the maintenance of tissue homeostasis and host defense against bacteria, viruses and fungi. In recent times, NLRs have been increasingly acknowledged as much more than innate sensors and have emerged also as relevant players in diseases classically defined by their adaptive immune responses such as asthma. In this review article, we discuss the current knowledge and recent developments about NLR expression, activation and function in relation to asthma and examine the potential interventions in NLR signaling as asthma immunomodulatory therapies.

• No association was found between NOD1 rs2075820 C>T polymorphism and HCC in the Moroccan population. • NOD2 rs718226 A>G was significantly associated with increased HCC development and progression risk. • Potential gender-specific differences regarding susceptibility and progressing toward HCC. Nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population. Genotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls. The NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01–4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15–4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (OR ad = 2.58; CI=1.26–5.31; P ad ​ = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (OR ad = 1.50; CI=1.07–2.09; P ad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (OR ad = 4.63; CI=1.53–14.00 vs. OR ad = 2.73; CI=1.05–7.09). The NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression. [ABSTRACT FROM AUTHOR]

As an ancient species with both conservation and commercial value, Sturgeon's inflammatory regulation mechanism is a research point. Nucleotide-binding and oligomerization domain-containing proteins 1 and 2 (NOD1/2) are classical intracellular pattern recognition receptors (PRRs) in immunity of anti-bacterial infection. However, the characterization and function of NOD1/2 in Sturgeon are still unclear. In this study, we analyzed the synteny relationship of NOD1/2 genes between Acipenser ruthenus and representative fishes at the genome-level. Results showed that the Ar NOD2 collinear genes pair was present in all representative fishes. The duplicated Ar NOD1/2 genes were under purifying selection during evolution as indicated by their Ka/Ks values. To explore the function of NOD1/2, we further investigated their expression patterns and the effects of pathogenic infection, PAMPs treatment, and siRNA interference in Acipenser baerii , the sibling species of A. ruthenus. Results showed that both Ab NOD1/2 were expressed at early developmental stages and in different tissues. Pathogenic infection in vivo and PAMPs treatment in vitro demonstrated that Ab NOD1/2 could respond to pathogen stimulation. siRNA interference with Ab NOD1/2 inhibited expression levels of RIPK2 and inflammatory cytokines compared to the control group after iE-DAP or MDP treatment. This study hinted that the Ab NOD1/2 could stimulate the inflammatory cytokines response during evolutionary processes. • ● Ar NOD1 and Ar NOD2 genes were under purifying selection during evolution. • ● Ab NOD1 and Ab NOD2 were expressed at early developmental stages and in different tissues. • Ab NOD1 and Ab NOD2 could respond to pathogen by mediate expression levels of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Abstract Background Triple negative breast cancer (TNBC) is a malignancy with very poor prognosis, due to its aggressive clinical characteristics and lack of response to receptor-targeted drug therapy. In TNBC, immune-related pathways are typically upregulated and may be associated with a better prognosis of the disease, encouraging the pursuit for immunotherapeutic options. A number of immune-related molecules have already been associated to the onset and progression of breast cancer, including NOD1 and NOD2, innate immune receptors of bacterial-derived components which activate pro-inflammatory and survival pathways. In the context of TNBC, overexpression of either NOD1or NOD2 is shown to reduce cell proliferation and increase clonogenic potential in vitro. To further investigate the pathways linking NOD1 and NOD2 signaling to tumorigenesis in TNBC, we undertook a global proteome profiling of TNBC-derived cells ectopically expressing each one of these NOD receptors. Results We have identified a total of 95 and 58 differentially regulated proteins in NOD1- and NOD2-overexpressing cells, respectively. We used bioinformatics analyses to identify enriched molecular signatures aiming to integrate the differentially regulated proteins into functional networks. These analyses suggest that overexpression of both NOD1 and NOD2 may disrupt immune-related pathways, particularly NF-κB and MAPK signaling cascades. Moreover, overexpression of either of these receptors may affect several stress response and protein degradation systems, such as autophagy and the ubiquitin-proteasome complex. Interestingly, the levels of several proteins associated to cellular adhesion and migration were also affected in these NOD-overexpressing cells. Conclusions Our proteomic analyses shed new light on the molecular pathways that may be modulating tumorigenesis via NOD1 and NOD2 signaling in TNBC. Up- and downregulation of several proteins associated to inflammation and stress response pathways may promote activation of protein degradation systems, as well as modulate cell-cycle and cellular adhesion proteins. Altogether, these signals seem to be modulating cellular proliferation and migration via NF-κB, PI3K/Akt/mTOR and MAPK signaling pathways. Further investigation of altered proteins in these pathways may provide more insights on relevant targets, possibly enabling the immunomodulation of tumorigenesis in the aggressive TNBC phenotype.

The receptor-interacting protein kinases (RIPKs) are key regulators of inflammatory signalling and cell death pathways triggered by innate immune receptors, and RIPKs have emerged as promising therapeutic targets for treatment of immune-related disorders. RIPK2 mediates signalling responses initiated by the bacterial-sensing pattern recognition receptors nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2), which play a key role in regulation of intestinal immunity and inflammation. Modification of RIPK2 by non-degradative ubiquitin chains generated by the E3 ubiquitin ligase XIAP and other ligases govern NOD1/2 signalling. Recent advances suggest that the interaction between RIPK2 and XIAP is a druggable protein-protein interaction to modulate NOD1/2-dependent immune responses. Here, we discuss the mechanistic function of RIPK2 in immune signalling, its clinical relevance, and the on-going efforts to target RIPK2 in inflammatory bowel disease and beyond. [ABSTRACT FROM AUTHOR]

Abstract Background NOD-like receptors (NLRs) are a family of cytoplasmic pattern recognition receptors (PRRs), of which NOD1 and NOD2, are the main representative members. Many investigations have focused on the role of NOD1 and NOD2 in the innate immune response in Cypriniformes and Siluriformes. As an important economic fish in Perciformes, little is known about the function of NOD1 and NOD2 in mandarinfish (Siniperca chuatsi). Results The full-length NOD1 and NOD2 cDNA sequence was obtained using reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The mandarinfish NOD1 and NOD2 cDNA sequences contain 3247 bp and 3257 bp, and encode 918 amino acids and 988 amino acids, respectively. Multiple sequence alignments showed that mNOD1 and mNOD2 share high similarity with that from other vertebrates. RT-PCR analysis revealed that relatively high levels of mNOD1 and mNOD2 mRNA were detected in gill and head kidney tissues, compared with the heart, spleen, liver, muscle, and intestine. In addition, the relative levels of mNOD1 and mNOD2 transcripts were significantly upregulated in three tissues when the fishes were challenged with LPS and Poly I:C, interestingly, the NOD1 mRNA got peaked earlier than NOD2 after LPS induction in the spleen, gill, and head kidney, and during Poly I:C treatment, the NOD2 mRNA got peaked at 8 h in spleen and gill, while NOD1 showed significant higher expression at 24 h post infection, besides, in head kidney, the NOD2 mRNA showed a great increasing trend and NOD1 got peaked at 16 h. Therefore the mNOD1 and mNOD2 may act differently within different tissues in different time during antiviral and antibacterial defense. Conclusions These results revealed the dynamic mNOD1 and mNOD2 expression during viral and bacterial infections, which suggested the NOD1 and NOD2 play important roles in innate immune of mandarinfish.

Abstract Objective Immune-related pathways have been frequently associated to tumorigenesis. NOD1 and NOD2 are innate immune receptors responsible for sensing a subset of bacterial-derived components, and to further translate these pathogenic signals through pro-inflammatory and survival pathways. NOD1 and NOD2 have been further associated with tumorigenesis, particularly in gastrointestinal cancers. NOD1 has also been suggested to be a tumor suppressor gene in a model of estrogen receptor-dependent breast cancer. Contrarily, NOD2 polymorphisms are associated with higher risk of breast cancer, with no tumor suppressor role being reported. To better delineate this issue, we investigated NOD1 and NOD2 expression in a panel of breast cancer cell lines, as well as their potential impact in breast tumorigenesis based on in vitro assays. Results The highly invasive Hs578T breast cell line presented the second highest NOD1 expression and the lowest NOD2 expression in our panel. Therefore, we investigated whether NOD1 and/or NOD2 might act as a tumor suppressor in this cell model. Our studies indicate that overexpression of either NOD1 or NOD2 reduces cell proliferation and increases clonogenic potential in vitro. Elucidation of NOD1 and NOD2 effects on tumor cell viability and proliferation may unveil potential targets for future therapeutic intervention.

Abstract Background Chronic kidney disease (CKD) is characterized by sustained tissue damage and ongoing tubulo-interstitial inflammation and fibrosis. Pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) can sense endogenous ligands released upon tissue damage, leading to sterile inflammation and eventually irreversible kidney disease. It is known that NOD1 and NOD2 contribute to the pathogenesis of various inflammatory diseases, including acute kidney injury. However their role in chronic kidney disease is largely unknown. The aim of this study was therefore to investigate the contribution of NOD1 and NOD2 in renal interstitial fibrosis and obstructive nephropathy. Methods To do so, we performed unilateral ureteral obstruction (UUO) in wild type (WT) and NOD1/NOD2 double deficient (DKO) mice and analysed renal damage, fibrosis and inflammation. Data were analysed using the non-parametric Mann-Whitney U-test. Results Minor changes in inflammatory response were observed in NOD1/2 DKO mice, while no effects were observed on renal injury and the development of fibrosis. Conclusion No difference in renal injury and fibrosis between WT and NOD1/NOD2 DKO mice following obstructive nephropathy induced by ureteral obstruction.

It has been long recognized that NOD1 and NOD2 are critical players in the host immune response, primarily by their sensing bacterial peptidoglycan‐conserved motifs. Significant advances have been made from efforts that characterize their upstream activators, assembly of signaling complexes, and activation of downstream signaling pathways. Disruption in NOD1 and NOD2 signaling has also been associated with impaired host defense and resistance to the development of inflammatory diseases. In this review, we will describe how NOD1 and NOD2 sense microbes and cellular stress to regulate host responses that can affect disease pathogenesis and outcomes. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa. The present study investigated the expression of nucleotide-binding oligomerization domain (NOD), a pivotal sensor protein of the innate immune system, in OLP. Oral mucosal biopsies were collected from 20 patients with OLP and 6 individuals with normal oral mucosa (NOM). The expression of NOD1 and NOD2 was determined using RT-PCR and immunohistochemistry in OLP and NOM samples. The mRNA expression of NOD1 and NOD2 was significantly higher in the OLP group than in the NOM group. The protein expression of NOD1 was marginally upregulated in all mucosal layers in the OLP group compared with that of the NOM group; however, the differences were not significant. The expression of NOD2 was elevated in infiltrating lymphocytes of the submucosal layer in the OLP group compared with the NOM group, but was undetected in other inflammatory disease, inflammatory fibrous hyperplasia (IFH). This study revealed the upregulation of NOD2 mRNA and protein in the OLP group, but not in the NOM group. These findings suggest that NOD2 may play an important role in the pathogenesis of OLP and represents a new diagnostic and treatment target. [ABSTRACT FROM AUTHOR]

Muramyl peptides are fragments of bacterial peptidoglycan playing an important role in the activation of innate immune system. Core structure of muramyl peptides is composed of N-acetylmuramic acid residue (MurNAc) covalently bound to a peptide consisting of 2-5 amino acid residues. The first residue in the peptide chain is usually L-alanine, the 2nd is D-isoglutamine or D-isoglutamic acid, the 4th and 5th are D-alanines. The 3rd residue is most variable being represented by L-lysine or L-ornithine in Gram-positive bacteria, or by meso-diaminopimelic acid (meso-DAP) in Gram-negative bacteria. Muramyl peptides are potential immunostimulants and adjuvants. Two receptors, NOD1 and NOD2, are known to play a central role in muramyl peptide recognition. However, the data on NOD receptor specificity for several common muramyl peptides are not available or incomplete.The goal of this study was to extend knowledge on possible relationships between structure of natural, or chemically modified muramyl peptides, and their selectivity towards NOD1 and NOD2 receptors.We investigated ability of natural muramyl peptides and their derivatives to activate NOD1 and NOD2. To this end, we used a novel biological test system, which represents modified HEK293T cells with NF-κB-driven reporter gene (luciferase) expression and knock-outs of endogenous NOD1 and/or NOD2 genes. As a result, we have shown that NOD2 has a broader spectrum of natural agonists than previously thought. In particular, NOD2 recognizes muramyl peptides from Gram-negative bacteria containing a meso-DAP residue, which have been considered inactive towards NOD2. NOD1 recognizes only muramyl peptides containing a mesoDAP residue; however, this molecule should not be exposed as a terminal residue, as thought earlier, but it may also be present within the peptide chain. This data imply that natural muramyl peptides containing mesoDAP have a dual receptor specificity (NOD1 and NOD2), i.e. they are non-selective NOD receptor agonists.Destruction of the MurNAc residue eliminates ability of these muramyl peptides to activate NOD2, but has no effect on their NOD1 agonism. Hence, modified muramyl peptides containing meso-DAP and a destroyed MurNAc residue are selective NOD1 agonists. Natural muramyl peptides featuring an intact MurNAc and no meso-DAP are selective NOD2 agonists.Conclusions: 1) we have characterized key structural features of selective NOD1 and NOD2 agonists as well as non-selective NOD receptors agonists; 2) we show the importance of these new data for understanding innate immune response regulation, and for development of novel muramyl peptide immunostimulants.

Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide‐binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD‐dependent and TLR‐dependent signaling pathways; and (iii) interactions at the post‐transcriptional level. Potential practical implications of NOD‐TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens. NOD1/NOD2 and TLRs synergize at induction of innate immune responses, which can be beneficial (boosting protective immunity) or deleterious (in sepsis). [ABSTRACT FROM AUTHOR]

Abstract Agonists of nucleotide oligomerization domain (NOD) 1 and NOD2 receptors represent a promising class of immunostimulants and immunological adjuvants. Here, we describe a cell-based test system to assess their pharmacokinetics. In this system, NOD1 and NOD2 agonist concentrations in sera are determined using a reporter cell line, 293Luc, which contains an NF-κB-inducible luciferase reporter construct and naturally expresses NOD1 and NOD2. The 293Luc cells dose-dependently respond to different NOD1 and NOD2 agonists in the nanomolar to low-micromolar concentration range. To verify that the NF-κB-inducing activity of serum samples is due to the administered agonist and not to secondarily induced endogenous molecules, a 293Luc-derived NOD1/NOD2 double-knockout clone is used. Within-run and between-run precisions of the system are <15% and <20%, respectively. Applicability of the novel assay is illustrated by studying pharmacokinetics of two specific NOD2 agonists ( N ‑acetyl‑ d ‑glucosaminyl‑ N ‑acetyl‑ d ‑muramyl‑ l ‑alanyl‑ d ‑isoglutamine and N ‑glycolyl‑ d ‑muramyl‑ l ‑alanyl‑ d ‑isoglutamine) and a specific NOD1 agonist ( N ‑acetyl‑ d ‑glucosaminyl‑ N ‑acetyl‑ d ‑sorbitolamine‑ d ‑lactoyl‑ l ‑alanyl‑ d ‑isoglutamyl‑ meso ‑diaminopimelic acid). In summary, the test system described here can potentially be used to assess pharmacokinetics of NOD1 and NOD2 agonists in different animal species. Highlights • A cell-based system to assess pharmacokinetics of NOD1 and NOD2 agonists is proposed. • NOD1/NOD2 agonist concentrations in sera are measured by a 293Luc reporter cell line. • 293Luc cells dose-dependently respond to nanomolar concentrations of the agonists. • A 293Luc-derived NOD1/NOD2 double-knockout clone is used as a specificity control. • Within-run and between-run precisions are <15% and <20%, respectively. [ABSTRACT FROM AUTHOR]

NOD like receptors (NLR) are essential pathogen associated molecular pattern receptors of cytoplasmic origin. During several intracellular parasitic infections NLR played vital role for host protective immune response against the pathogen. Amongst various classes of NLR, NOD1 and NOD2 had been extensively studied and were found to be the most active member of the NLR family. Therefore, we wanted to study the role of NOD1/NOD2 during Leishmania donovan i infection and the mechanism behind the utilization of this pathway as a therapeutic approach. Using the infected model of macrophage and BALB/c mice the expression of NOD1 and NOD2 were analysed. Our study showed that NOD2 but not NOD1 has been exploited during experimental VL, leading to the imbalance between Th-1/Th-2 cytokines profile. Over-expression of NOD2 and stimulation with its ligand muramyl dipeptide leads to successful clearance of parasite. During in vivo experiments we found that arabinosylated lipoarabinomannan helps in the restoration of NOD2 and with MDP in combination leads to effective clearance of parasite which rescued host protective immunity and comparatively more effective than Mw and MDP combination resulting in increase T cell response. Consequently, our study highlighted the significance of NOD2 during infection the immune-modulations of which can be used as a therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is characterized by sustained tissue damage and ongoing tubulo-interstitial inflammation and fibrosis. Pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) can sense endogenous ligands released upon tissue damage, leading to sterile inflammation and eventually irreversible kidney disease. It is known that NOD1 and NOD2 contribute to the pathogenesis of various inflammatory diseases, including acute kidney injury. However their role in chronic kidney disease is largely unknown. The aim of this study was therefore to investigate the contribution of NOD1 and NOD2 in renal interstitial fibrosis and obstructive nephropathy.Methods: To do so, we performed unilateral ureteral obstruction (UUO) in wild type (WT) and NOD1/NOD2 double deficient (DKO) mice and analysed renal damage, fibrosis and inflammation. Data were analysed using the non-parametric Mann-Whitney U-test.Results: Minor changes in inflammatory response were observed in NOD1/2 DKO mice, while no effects were observed on renal injury and the development of fibrosis.Conclusion: No difference in renal injury and fibrosis between WT and NOD1/NOD2 DKO mice following obstructive nephropathy induced by ureteral obstruction. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain (NOD) 1 and NOD2 are pattern-recognition receptors responsible for sensing fragments of bacterial peptidoglycan known as muropeptides. Stimulation of innate immunity by systemic or local administration of NOD1 and NOD2 agonists is an attractive means to prevent and treat infectious diseases. In this review, we discuss novel data concerning structural features of selective and non-selective (dual) NOD1 and NOD2 agonists, main signaling pathways and biological effects induced by NOD1 and NOD2 stimulation, including induction of pro-inflammatory cytokines, type I interferons and antimicrobial peptides, induction of autophagy, alterations of metabolism. We also discuss interactions between NOD1/NOD2 and Toll-like receptor agonists in terms of synergy and cross-tolerance. Finally, we review available animal data on the role of NOD1 and NOD2 in protection against infections, and discuss how these data could be applied in human infectious diseases. [ABSTRACT FROM AUTHOR]

Thermotolerance depends mainly on the health and immune status of the animals. The variation in the immune status of the animals may alter the level of tolerance of animals exposed to heat or cold stress. The present study was conducted to investigate the expression profile of two important nucleotide binding and oligomerization domain receptors (NLRs) (NOD1 and NOD2) and their central signalling molecule RIP2 gene during in vitro thermal-stressed bovine peripheral blood mononuclear cells (PBMCs) of native (Sahiwal) and crossbred (Sahiwal X HF) cattle. We also examined the differential expression profile of certain acute inflammatory cytokines in in vitro thermal-stressed PBMC culture among native and its crossbred counterparts. Results revealed that the expression profile of NOD1/2 positively correlates with the thermal stress, signalling molecule and cytokines. Present findings also highlighted that the expression patterns during thermal stress were comparatively superior among indigenous compared to crossbred cattle which may add references regarding the better immune adaptability of Zebu cattle. [ABSTRACT FROM AUTHOR]

In mares, endometrial diseases are the main cause of reduced fertility and have a high financial impact on equine breeding. Of particular importance are subclinical diseases, since they can only be diagnosed by the histological examination of an endometrial biopsy. Moreover, the precise pathogenesis of some frequent subclinical diseases, i.e. nonsuppurative endometritis and endometrosis (periglandular fibrosis), is unknown. The reason for the increased susceptibility of some mares to develop a persistent postbreeding endometritis (PPBE) is also still unsolved. The nucleotide-binding oligomerization domain proteins 1 and 2 (NOD1 and NOD2) are innate immunity receptors of epithelial and antigen presenting cells. On the one hand, they defend against intracellular bacteria and thus help to prevent and clear tissue infections. On the other hand, their altered expression can contribute to tissue inflammation and fibrosis. It has been shown that NOD1 and NOD2 are also involved in the pathogenesis of uterine diseases in women and other species. To the best of the authors' knowledge, no data are published in regard to the expression of NOD1 and NOD2 in the equine endometrium. The aim of this study was to examine if NOD1 and NOD2 transcripts are expressed in the healthy and diseased equine endometrium. Endometrial samples of 31 adult mares were investigated by PCR and histology. The former was performed in comparison on native and formalin-fixed paraffinembedded (FFPE) samples. By PCR, transcripts of NOD1 and NOD2 were detected in native and FFPE endometrial samples of all 31 mares. The morphology of endometrial glands was secretory (n=19), proliferative (n=6) or in transition between both stages (n=6). Five tissue samples had no pathological alterations; two of these were from a gravid mare. The remaining showed one or several endometrial diseases including different forms of endometritis (n=12), endometrosis (n=20), angiosclerosis (n=20), perivasculitis and vasculitis (n=1), infiltration with neoplastic lymphocytes (n=1) and placental retention (n=1). Results of this study are consistent with a constitutive expression of NOD1 and NOD2 transcripts during all stages of the endometrial cycle within the healthy and diseased equine endometrium. They imply a functional importance of NOD1 and NOD2 in the equine endometrium for the regulation of physiological processes as well as the pathogenesis of endometrial diseases. In human beings, certain polymorphisms and mutations of NOD genes have been identified as predisposing factors for chronic inflammation. Thus, it appears possible that NOD gene polymorphisms may also contribute to the resistance or susceptibility of mares to develop PPBE. This study provides the basis for future investigation into the contribution of NOD1 and NOD2 to the pathogenesis of equine endometrial diseases. The results of those future studies may reveal information that is beneficial for the prevention and treatment of equine endometrial diseases. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain ( NOD) -like receptors ( NLRs) are a family of 23 receptors known as pattern recognition receptors; they are expressed in many cell types and play a key role in the innate immune response. The NLRs are activated by pathogen-associated molecular patterns, which include structurally conserved molecules present on the surfaces of bacteria. The activation of these NLRs by pathogens results in the downstream activation of signalling kinases and transcription factors, culminating in the transcription of genes coding for pro-inflammatory factors. Expression of NLR is altered in many cellular, physiological and disease states. There is a lack of understanding of the mechanisms by which NLR expression is regulated, particularly in chronic inflammatory states. Genetic polymorphisms and protein interactions are included in such mechanisms. This review seeks to examine the current knowledge regarding the regulation of this family of receptors and their signalling pathways as well as how their expression changes in disease states with particular focus on NOD1 and NOD2 in inflammatory bowel diseases among others. [ABSTRACT FROM AUTHOR]

What is known and objective Nucleotide-binding oligomerization domain ( NOD) 1 and NOD 2 are members of the NOD-like receptor ( NLR) family and contain a caspase recruitment domain. NLRs are located in the cytosol, bind bacterial and viral ligands and play a key role in the realization of innate and adaptive immune response, inflammation, apoptosis and reactive oxygen species generation. Insulin resistance ( IR) is a leading cause of type 2 diabetes mellitus (T2 DM) and associated with obesity, inflammation and pro-inflammatory responses. NOD1 and NOD2 gene variants may affect the risk of chronic inflammation, insulin resistance and T2 DM by shifting the balance between pro- and anti-inflammatory cytokines. The aim of our study was to determine whether the NOD1/2 gene variants might contribute to the risk of T2 DM and IR. Methods The rs5743336 variant of NOD1 and rs2066847 variant of NOD2 were analysed by PCR- RFLP analysis in 200 subjects (T2 DM: n = 100; healthy controls: n = 100) of Turkish origin. PCR products were digested with the AvaI and ApaI restriction enzymes. For the NOD1 site, the presence of the G allele was indicated by cleavage of the 379 bp amplified PCR product that yielded 209-bp and 170-bp fragments. For the NOD2 site, 151-bp PCR products were cleaved and yielded 130-bp and 21-bp fragments when the WT-insC mutation was present. Comparisons of the genotypes between controls and patients were performed by chi-square tests. Results and discussion The genotypes of the rs5743336 variant of NOD1 and the rs2066847 variant of NOD2 are presented, and no significant differences were observed in the genotype frequencies of the NOD1 and NOD2 variants between the healthy controls and T2 DM patients ( P > 0·05). According to our preliminary data, NOD1/2 gene variants are not linked with T2 DM and IR. What is new and conclusion This study is the first to look for possible association of the genotype frequencies of NOD1 and NOD2 genes with T2 DM and IR. The significant finding of this report is that the rs5743336 and rs2066847 variations in the NOD1/2 gene are not associated with T2 DM and IR risk in patients of Turkish origin. [ABSTRACT FROM AUTHOR]

Chlamydial species are common intracellular parasites that cause various diseases, mainly characterized by persistent infection, which lead to inflammatory responses modulated by pattern recognition receptors (PRRs). The best understood PRRs are the extracellular Toll-like receptors, but recent significant advances have focused on two important proteins, NOD1 and NOD2, which are members of the intracellular nucleotide-binding oligomerization domain receptor family and are capable of triggering the host innate immune signaling pathways. This results in the production of pro-inflammatory cytokines, which is vital for an adequate host defense against intracellular chlamydial infection. NOD1/2 ligands are known to derive from peptidoglycan, and the latest research has resolved the paradox of whether chlamydial species possess this bacterial cell wall component; this finding is likely to promote in-depth investigations into the interaction between the NOD proteins and chlamydial pathogens. In this review, we summarize the basic characteristics and signal transduction functions of NOD1 and NOD2 and highlight the new research on the roles of NOD1 and NOD2 in the host defense against chlamydial infection. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) play an important role in host anti-donor responses to transplanted tissue. A key trigger of the host alloresponse involves recognition of foreign antigen presented on activated antigen presenting cells by the host T cells. Emerging data suggest that PRR blockade can abrogate host anti-donor responses by interfering with activation of antigen presenting cells, particularly activation of dendritic cells. Our study asked whether blockade of a well-characterized family of intracellular PRRs, the NOD family, interfered with alloantigen recognition and allograft rejection. We found that deletion of either NOD1 or NOD2 in antigen presenting cells (APCs) had no effect on induction of T cell proliferation to alloantigen, but that simultaneous deletion of NOD1 and NOD2 significantly inhibited T cell responses. There was however no effect of the NOD deletion on skin graft rejection when NOD1 × NOD2 skin was transplanted onto allogeneic hosts or when WT skin was transplanted onto NOD1 × NOD2 deficient recipients. The conclusion of this study is that in vitro alloresponses are negatively impacted by the simultaneous deletion of NOD1 and NOD2, but that allograft rejection across a stringent allo barrier is not affected. Our results suggest that the NOD family members, NOD1 and NOD2, play a collaborative role in T cell activation by alloantigen and that their blockade in vitro can inhibit T cell responses. [ABSTRACT FROM AUTHOR]

The nucleotide-binding oligomerization domain proteins NOD1 and NOD2 are important cytoplasmic pathogen recognition receptors which sense microbial infections molecules to induce innate immune response. In this study, the sequence analysis showed that NOD1 and NOD2 genes in miiuy croaker ( miichthys miiuy , mmiNOD1 and mmiNOD2) share some highly conserved motifs that crucial for recognizing the bacterial and viral components. Quantitative expression analysis revealed mmiNOD1 and mmiNOD2 had the highest level of expression in liver. Induction experiments with Vibrio anguillarum indicated the different expression levels of mmiNOD1 and mmiNOD2 in liver, spleen and kidney. The expressions of mmiNOD1 and mmiNOD2 increased more significantly after Poly(I:C) stimulation, meanwhile, we carried out the expression analysis at the transcriptome level and the regulation of microRNAs. In addition, the evolutionary analysis showed that the ancestral lineages of NOD1 in bony fish detected one positively selected site, however, both the current lineages of NOD1 and NOD2 genes in bony fish underwent purifying selection indicating that NOD1 gene in the ancestor of bony fish experienced positive selection. To further understand the evolutionary pattern of NOD1 and NOD2 in vertebrates, we were the first to conduct comparative genomic analysis by comparing the number and synteny of NOD1 and NOD2. Combining the duplication of NOD1, the lost of NOD2 and the more conserved synteny of NOD2 than NOD1, we proposed that the hypothetical evolutionary pattern is different between NOD1 and NOD2. [ABSTRACT FROM AUTHOR]

Introduction Nucleotide binding and oligomerization leucine-rich repeats (NLR) are recognized as members of pattern-recognition receptors that play important roles in host innate immune defenses. In this study, we have investigated the expression and regulation of nucleotide-binding oligomerization domains 1 and 2 (NOD1 and NOD2) on the invasiveness of primary human trophoblasts during the first trimester of pregnancy. Methods The expression of NOD1 and NOD2 by human first trimester villi from recurrent spontaneous abortion (RSA) patients and normal pregnancy was analyzed by immunochemistry, western blot and real-time RT-PCR, respectively. The effects of ligands on the regulation of their receptors and invasiveness of trophoblasts were examined. The ELISA was used to measure the secretion of matrix matallopeptidase-9 (MMP9) and matrix matallopeptidase-2 (MMP2) by trophoblasts. We also investigated the signaling pathways involved in invasion of trophoblasts. Results The higher NOD1 and NOD2 were observed in villi from patients who experienced RSA compared with those who experienced a normal pregnancy. The ligands can up-regulate the expression of their receptors. After activation, NOD1 and NOD2 inhibited the invasion of trophoblast cells by decreasing MMP9 but not MMP2. After the activation of NOD1 and NOD2, the mitogen-activated protein kinase (MAPK)/p38 pathway was activated time dependently. Blocking this pathway with a specific inhibitor (SB203580) attenuated NOD1-and NOD2-regulated trophoblast invasions. Discussion These results suggest that abnormal elevated NOD1 and NOD2 expression in villi relate to pregnancy outcomes. Further, activation of NOD1 and NOD2 could have a bearing on our understanding of the invasive ability of trophoblasts. [ABSTRACT FROM AUTHOR]

Intracellular pattern-recognition receptors NOD1 and NOD2 are capable of sensing common structural units of bacterial walls. Recognition triggers specific immune signalling pathways and leads to pro-inflammatory cytokine upregulation and adequate immune response. We investigated whether two functional polymorphisms in NOD1 and NOD2 exert an effect on susceptibility to (STD patients) and severity of (female patients visiting the fertility clinic) Chlamydia trachomatis infection in 807 Dutch Caucasian women. A significant association of the NOD1 +32656 GG insertion variant with protection against infection with C. trachomatis has been detected [p: 0.0057; OR: 0.52]. When comparing C. trachomatis-positive women without symptoms to C. trachomatis-positive women with symptoms, and to C. trachomatis-positive women with TFI, we observed an increasing trend in carriage of the GG allele [Ptrend: 0.0003]. NOD2 1007fs failed to reveal an association. We hypothesize that the underlying mechanism might be a functional effect of the GG insertion on IFN-beta-dependent regulation of immune response in the genital tract. The research is part of an ongoing effort of identifying key polymorphisms that determine the risk of TFI and effectively translating them into the clinical setting for the purpose of optimizing diagnostic management of women at risk for developing TFI. [ABSTRACT FROM AUTHOR]