The Experts below are selected from a list of 58179 Experts worldwide ranked by ideXlab platform
Gabriel Nunez - One of the best experts on this subject based on the ideXlab platform.
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innate immunity er stress recruits NOD1 and nod2 for delivery of inflammation
Current Biology, 2016Co-Authors: Roberta Caruso, Gabriel NunezAbstract:NOD1 and NOD2, two members of the intracellular NOD-like receptor family, sense bacterial peptidoglycan-derived fragments and induce pro-inflammatory responses. Recent work provides evidence for a role for NOD1/NOD2 signaling in mediating ER-stress-induced inflammatory responses via a peptidoglycan-independent mechanism.
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role of nucleotide binding oligomerization domain 1 NOD1 in pericyte mediated vascular inflammation
Journal of Cellular and Molecular Medicine, 2016Co-Authors: Rocío Navarro, Gabriel Nunez, Marta Compte, Pablo Delgadowicke, Natalia Nunezprado, Ana Blancotoribio, Luis Alvarezvallina, Laura SanzAbstract:We have recently described the response of human brain pericytes to lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4). However, Gram-negative pathogen-associated molecular patterns include not only LPS but also peptidoglycan (PGN). Given that the presence of co-purified PGN in the LPS preparation previously used could not be ruled out, we decided to analyse the expression of the intracellular PGN receptors NOD1 and NOD2 in HBP and compare the responses to their cognate agonists and ultrapure LPS. Our findings show for the first time that NOD1 is expressed in pericytes, whereas NOD2 expression is barely detectable. The NOD1 agonist C12-iE-DAP induced IL6 and IL8 gene expression by pericytes as well as release of cytokines into culture supernatant. Moreover, we demonstrated the synergistic effects of NOD1 and TLR4 agonists on the induction of IL8. Using NOD1 silencing in HBP, we showed a requirement for C12-iE-DAP-dependent signalling. Finally, we could discriminate NOD1 and TLR4 pathways in pericytes by pharmacological targeting of RIPK2, a kinase involved in NOD1 but not in TLR4 signalling cascade. p38 MAPK and NF-κB appear to be downstream mediators in the NOD1 pathway. In summary, these results indicate that pericytes can sense Gram-negative bacterial products by both NOD1 and TLR4 receptors, acting through distinct pathways. This provides new insight about how brain pericytes participate in the inflammatory response and may have implications for disease management.
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Role of nucleotide‐binding oligomerization domain 1 (NOD1) in pericyte‐mediated vascular inflammation
Journal of cellular and molecular medicine, 2016Co-Authors: Rocío Navarro, Gabriel Nunez, Pablo Delgado-wicke, Natalia Nuñez-prado, Marta Compte, Ana Blanco-toribio, Luis Álvarez-vallina, Laura SanzAbstract:We have recently described the response of human brain pericytes to lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4). However, Gram-negative pathogen-associated molecular patterns include not only LPS but also peptidoglycan (PGN). Given that the presence of co-purified PGN in the LPS preparation previously used could not be ruled out, we decided to analyse the expression of the intracellular PGN receptors NOD1 and NOD2 in HBP and compare the responses to their cognate agonists and ultrapure LPS. Our findings show for the first time that NOD1 is expressed in pericytes, whereas NOD2 expression is barely detectable. The NOD1 agonist C12-iE-DAP induced IL6 and IL8 gene expression by pericytes as well as release of cytokines into culture supernatant. Moreover, we demonstrated the synergistic effects of NOD1 and TLR4 agonists on the induction of IL8. Using NOD1 silencing in HBP, we showed a requirement for C12-iE-DAP-dependent signalling. Finally, we could discriminate NOD1 and TLR4 pathways in pericytes by pharmacological targeting of RIPK2, a kinase involved in NOD1 but not in TLR4 signalling cascade. p38 MAPK and NF-κB appear to be downstream mediators in the NOD1 pathway. In summary, these results indicate that pericytes can sense Gram-negative bacterial products by both NOD1 and TLR4 receptors, acting through distinct pathways. This provides new insight about how brain pericytes participate in the inflammatory response and may have implications for disease management.
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NOD1 and nod2 signaling host defense and inflammatory disease
Immunity, 2014Co-Authors: Roberta Caruso, Naohiro Inohara, Neil Warner, Gabriel NunezAbstract:The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
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viral infection augments NOD1 2 signaling to potentiate lethality associated with secondary bacterial infections
Cell Host & Microbe, 2011Co-Authors: Yun Gi Kim, Jong Hwan Park, Thornik Reimer, Darren P Baker, Taro Kawai, Himanshu Kumar, Shizuo Akira, Christiane E Wobus, Gabriel NunezAbstract:Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs NOD1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced NOD1 and Nod2 signaling by poly I:C required the TLR3/MDA5 adaptors TRIF and IPS-1 and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-β induced the expression of NOD1, Nod2, and the Nod-signaling adaptor Rip2. Systemic administration of poly I:C or IFN-β or infection with murine norovirus-1 promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden but attenuated in the absence of NOD1/Nod2 or Rip2. Thus, crosstalk between type I IFNs and NOD1/Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.
Dana J. Philpott - One of the best experts on this subject based on the ideXlab platform.
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NOD1 and NOD2 in inflammation, immunity and disease.
Archives of Biochemistry and Biophysics, 2019Co-Authors: Tapas Mukherjee, Dana J. Philpott, Elise Sofie Hovingh, Elisabeth G. Foerster, Mena Abdel-nour, Stephen E. GirardinAbstract:Abstract NOD1 and NOD2 are related intracellular sensors of bacterial peptidoglycan and belong to the Nod-like receptor (NLR) family of innate immune proteins that play fundamental and pleiotropic roles in host defense against infection and in the control of inflammation. The importance of these proteins is also highlighted by the genetic association between single nucleotide polymorphisms in NOD2 and susceptibility to Crohn's disease, an inflammatory bowel disease. At the cellular level, recent efforts have delineated the signaling pathways triggered following activation of NOD1 and NOD2, and the interplay with various cellular processes, such as autophagy. In vivo studies have revealed the importance of NOD-dependent host defense in models of infection, and a crucial area of investigation focuses on understanding the role of NOD1 and NOD2 at the intestinal mucosa, as this is of prime importance for understanding the etiology of Crohn's disease.
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NOD proteins: regulators of inflammation in health and disease
Nature Reviews Immunology, 2014Co-Authors: Dana J. Philpott, Matthew T. Sorbara, Susan J. Robertson, Kenneth Croitoru, Stephen E. GirardinAbstract:Nucleotide oligomerization domain-containing protein 1 (NOD1) and NOD2 are pattern-recognition receptors that detect bacterial peptidoglycan. Signalling through NODs initiates a variety of effector immune responses that seem to be crucial for maintaining immune homeostasis with the host microbiota. Indeed, mutations in NOD1 and NOD2 are associated with both intestinal and extra-intestinal disease. This Review summarizes our current understanding of the NODs. NOD1 (nucleotide oligomerization domain-containing protein 1) and NOD2 are members of the NOD-like receptor family of proteins, which function to detect peptidoglycan and to stimulate host responses to limit bacterial infection. The link between NOD2 and the inflammatory bowel disease Crohn's disease highlights the importance of maintaining balanced innate immune responses through NOD signalling in response to the host microbiota at the intestinal mucosa. NOD proteins react to peptidoglycan fragments that enter into the host cytosol by a variety of mechanisms, including direct infection by cyto-invasive pathogens, delivery through bacterial outer membrane vesicles or type IV secretion systems, and through membrane oligopeptide transporters, including solute carrier family 15 member 4 (SLC15A4) and pH-sensing regulatory factor of peptide transporter 1 (PEPT1). Fragments of peptidoglycan can bind to NOD1 and NOD2, inducing their self-association through their interaction at the nucleotide-binding domain (NBD). Oligomerization leads to the recruitment of receptor-interacting protein 2 (RIP2), which regulates the activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NOD signalling results in several downstream effects, including cytokine production, recruitment of neutrophils and inflammatory macrophages, and initiation of type 2 immunity. Mice that are deficient in the NOD signalling pathway have altered abilities to fight off bacterial infection. Interestingly, several pathogens have developed mechanisms to evade NOD-mediated immunity, including mechanisms that modify peptidoglycan. Autophagy is also affected by NOD signalling. NOD proteins mediate the detection of bacteria, such as Shigella flexneri , in the cytosol of infected cells and, through their interaction with a key autophagy protein called ATG16L1 (autophagy-related protein 16-like 1), can bring the autophagy machinery to the site where the bacteria reside in the cytosol. The induction of autophagy wraps cytosolic bacteria in autophagosomes that subsequently fuse with lysosomes to degrade the bacteria. The interaction of ATG16L1 with NOD1 and NOD2 also regulates the ability of the NODs to drive inflammatory signalling. Indeed, ATG16L1 is a negative regulator of NOD signalling and reduces cytokine production in a manner that is independent of autophagy. Most studies using mouse colitis models have shown that NODs have a protective role in intestinal inflammation. NODs maintain intestinal homeostasis by a variety of mechanisms including fortification of the intestinal barrier and regulation of early inflammatory pathways, such as those governed by interleukin-17 (IL-17), to limit infection and to promote mucosal healing. NOD signalling is also thought to influence the gut microbiota, although there is still controversy as to whether NOD deficiency itself or the underlying inflammation mediates changes in the gut microbial communities. NOD proteins also affect the development of extra-intestinal diseases and cancer. Polymorphisms in the genes that encode NOD1 and NOD2 have been linked to asthma and atopy, graft-versus-host disease, the auto-inflammatory disease Blau syndrome, and cancer. In the case of cancer, NOD deficiency promotes carcinogenesis by providing an inflammatory microenvironment that is exacerbated by chemicals, such as dextran sodium sulphate (DSS), that induce epithelial injury. Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo , NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
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NOD1 and nod2 enhance tlr mediated invariant nkt cell activation during bacterial infection
Journal of Immunology, 2013Co-Authors: Thirumahal Selvanantham, Dana J. Philpott, Stephen E. Girardin, Nichole K Escalante, Mayra Cruz Tleugabulova, Stephanie Fieve, Thierry MallevaeyAbstract:Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors NOD1 and Nod2 are necessary for optimal IFN-γ production by iNKT cells, as well as NK cells. In the absence of NOD1 and Nod2, iNKT cells had a blunted IFN-γ response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between NOD1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection.
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NOD1 Activators Link Innate Immunity to Insulin Resistance
Diabetes, 2011Co-Authors: Jonathan D. Schertzer, Joao G Magalhaes, Akhilesh K. Tamrakar, Sandra Pereira, Philip J. Bilan, Morgan D. Fullerton, Zhi Liu, Gregory R. Steinberg, Adria Giacca, Dana J. PhilpottAbstract:OBJECTIVE Insulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance. RESEARCH DESIGN AND METHODS Metabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2−/− double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid–containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand–injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro. RESULTS NOD1/2−/− mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1−/−, mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1−/−, mice. CONCLUSIONS We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism.
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NOD1 and Nod2 regulation of inflammation in the Salmonella colitis model.
Infection and immunity, 2010Co-Authors: Kaoru Geddes, Stephen E. Girardin, Joao G Magalhaes, Lionel Le Bourhis, Stephen Rubino, Catherine J. Streutker, Joon Ho Cho, Thirumahal Selvanantham, Dana J. PhilpottAbstract:The pattern recognition molecules NOD1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin-treated mouse model of Salmonella colitis, we found that mice deficient for both NOD1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. NOD1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, NOD1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS.
Stephen E. Girardin - One of the best experts on this subject based on the ideXlab platform.
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NOD1 and NOD2 in inflammation, immunity and disease.
Archives of Biochemistry and Biophysics, 2019Co-Authors: Tapas Mukherjee, Dana J. Philpott, Elise Sofie Hovingh, Elisabeth G. Foerster, Mena Abdel-nour, Stephen E. GirardinAbstract:Abstract NOD1 and NOD2 are related intracellular sensors of bacterial peptidoglycan and belong to the Nod-like receptor (NLR) family of innate immune proteins that play fundamental and pleiotropic roles in host defense against infection and in the control of inflammation. The importance of these proteins is also highlighted by the genetic association between single nucleotide polymorphisms in NOD2 and susceptibility to Crohn's disease, an inflammatory bowel disease. At the cellular level, recent efforts have delineated the signaling pathways triggered following activation of NOD1 and NOD2, and the interplay with various cellular processes, such as autophagy. In vivo studies have revealed the importance of NOD-dependent host defense in models of infection, and a crucial area of investigation focuses on understanding the role of NOD1 and NOD2 at the intestinal mucosa, as this is of prime importance for understanding the etiology of Crohn's disease.
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NOD proteins: regulators of inflammation in health and disease
Nature Reviews Immunology, 2014Co-Authors: Dana J. Philpott, Matthew T. Sorbara, Susan J. Robertson, Kenneth Croitoru, Stephen E. GirardinAbstract:Nucleotide oligomerization domain-containing protein 1 (NOD1) and NOD2 are pattern-recognition receptors that detect bacterial peptidoglycan. Signalling through NODs initiates a variety of effector immune responses that seem to be crucial for maintaining immune homeostasis with the host microbiota. Indeed, mutations in NOD1 and NOD2 are associated with both intestinal and extra-intestinal disease. This Review summarizes our current understanding of the NODs. NOD1 (nucleotide oligomerization domain-containing protein 1) and NOD2 are members of the NOD-like receptor family of proteins, which function to detect peptidoglycan and to stimulate host responses to limit bacterial infection. The link between NOD2 and the inflammatory bowel disease Crohn's disease highlights the importance of maintaining balanced innate immune responses through NOD signalling in response to the host microbiota at the intestinal mucosa. NOD proteins react to peptidoglycan fragments that enter into the host cytosol by a variety of mechanisms, including direct infection by cyto-invasive pathogens, delivery through bacterial outer membrane vesicles or type IV secretion systems, and through membrane oligopeptide transporters, including solute carrier family 15 member 4 (SLC15A4) and pH-sensing regulatory factor of peptide transporter 1 (PEPT1). Fragments of peptidoglycan can bind to NOD1 and NOD2, inducing their self-association through their interaction at the nucleotide-binding domain (NBD). Oligomerization leads to the recruitment of receptor-interacting protein 2 (RIP2), which regulates the activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NOD signalling results in several downstream effects, including cytokine production, recruitment of neutrophils and inflammatory macrophages, and initiation of type 2 immunity. Mice that are deficient in the NOD signalling pathway have altered abilities to fight off bacterial infection. Interestingly, several pathogens have developed mechanisms to evade NOD-mediated immunity, including mechanisms that modify peptidoglycan. Autophagy is also affected by NOD signalling. NOD proteins mediate the detection of bacteria, such as Shigella flexneri , in the cytosol of infected cells and, through their interaction with a key autophagy protein called ATG16L1 (autophagy-related protein 16-like 1), can bring the autophagy machinery to the site where the bacteria reside in the cytosol. The induction of autophagy wraps cytosolic bacteria in autophagosomes that subsequently fuse with lysosomes to degrade the bacteria. The interaction of ATG16L1 with NOD1 and NOD2 also regulates the ability of the NODs to drive inflammatory signalling. Indeed, ATG16L1 is a negative regulator of NOD signalling and reduces cytokine production in a manner that is independent of autophagy. Most studies using mouse colitis models have shown that NODs have a protective role in intestinal inflammation. NODs maintain intestinal homeostasis by a variety of mechanisms including fortification of the intestinal barrier and regulation of early inflammatory pathways, such as those governed by interleukin-17 (IL-17), to limit infection and to promote mucosal healing. NOD signalling is also thought to influence the gut microbiota, although there is still controversy as to whether NOD deficiency itself or the underlying inflammation mediates changes in the gut microbial communities. NOD proteins also affect the development of extra-intestinal diseases and cancer. Polymorphisms in the genes that encode NOD1 and NOD2 have been linked to asthma and atopy, graft-versus-host disease, the auto-inflammatory disease Blau syndrome, and cancer. In the case of cancer, NOD deficiency promotes carcinogenesis by providing an inflammatory microenvironment that is exacerbated by chemicals, such as dextran sodium sulphate (DSS), that induce epithelial injury. Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo , NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
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NOD1 and nod2 enhance tlr mediated invariant nkt cell activation during bacterial infection
Journal of Immunology, 2013Co-Authors: Thirumahal Selvanantham, Dana J. Philpott, Stephen E. Girardin, Nichole K Escalante, Mayra Cruz Tleugabulova, Stephanie Fieve, Thierry MallevaeyAbstract:Invariant NKT (iNKT) cells act at the crossroad between innate and adaptive immunity and are important players in the defense against microbial pathogens. iNKT cells can detect pathogens that trigger innate receptors (e.g., TLRs, Rig-I, Dectin-1) within APCs, with the consequential induction of CD1d-mediated Ag presentation and release of proinflammatory cytokines. We show that the cytosolic peptidoglycan-sensing receptors NOD1 and Nod2 are necessary for optimal IFN-γ production by iNKT cells, as well as NK cells. In the absence of NOD1 and Nod2, iNKT cells had a blunted IFN-γ response following infection by Salmonella enterica serovar Typhimurium and Listeria monocytogenes. For Gram-negative bacteria, we reveal a synergy between NOD1/2 and TLR4 in dendritic cells that potentiates IL-12 production and, ultimately, activates iNKT cells. These findings suggest that multiple innate pathways can cooperate to regulate iNKT cell activation during bacterial infection.
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Phenotyping of NOD1/2 double deficient mice and characterization of NOD1/2 in systemic inflammation and associated renal disease
Biology open, 2012Co-Authors: Ingrid Stroo, Stephen E. Girardin, Loes M. Butter, Nike Claessen, Gwen J. Teske, Stephen Rubino, Sandrine Florquin, Jaklien C. LeemansAbstract:It is indispensable to thoroughly characterize each animal model in order to distinguish between primary and secondary effects of genetic changes. The present study analyzed NOD1 and Nod2 double deficient (NOD1/2 DKO) mice under physiological and inflammatory conditions. NOD1 and Nod2 are members of the Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLR) family. Several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either NOD1 or Nod2. These associations suggest that NOD1 and Nod2 play important roles in regulating the immune system. Three-month-old wildtype (Wt) and NOD1/2 DKO mice were sacrificed, body and organ weight were determined, and blood was drawn. Except for lower liver weight in NOD1/2 DKO mice, no differences were found in body/organ weight between both strains. Leukocyte count and composition was comparable. No significant changes in analyzed plasma biochemical markers were found. Additionally, intestinal and vascular permeability was determined. NOD1/2 DKO mice show increased susceptibility for intestinal permeability while vascular permeability was not affected. Next we induced septic shock and organ damage by administering LPS+PGN intraperitoneally to Wt and NOD1/2 DKO mice and sacrificed animals after 2 and 24 hours. The systemic inflammatory and metabolic response was comparable between both strains. However, renal response was different as indicated by partly preserved kidney function and tubular epithelial cell damage in NOD1/2 DKO at 24 hours. Remarkably, renal inflammatory mediators Tnfα, KC and Il-10 were significantly increased in NOD1/2 DKO compared with Wt mice at 2 hours. Systematic analysis of NOD1/2 DKO mice revealed a possible role of NOD1/2 in the development of renal disease during systemic inflammation.
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NOD1 and Nod2 regulation of inflammation in the Salmonella colitis model.
Infection and immunity, 2010Co-Authors: Kaoru Geddes, Stephen E. Girardin, Joao G Magalhaes, Lionel Le Bourhis, Stephen Rubino, Catherine J. Streutker, Joon Ho Cho, Thirumahal Selvanantham, Dana J. PhilpottAbstract:The pattern recognition molecules NOD1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin-treated mouse model of Salmonella colitis, we found that mice deficient for both NOD1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. NOD1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, NOD1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS.
Naohiro Inohara - One of the best experts on this subject based on the ideXlab platform.
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synthesis of characteristic mycobacterium peptidoglycan pgn fragments utilizing with chemoenzymatic preparation of meso diaminopimelic acid dap and their modulation of innate immune responses
Organic and Biomolecular Chemistry, 2016Co-Authors: Naohiro Inohara, Yukari Fujimoto, Qianqian Wang, Yusuke Matsuo, Ambara R Pradipta, Koichi FukaseAbstract:Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of D-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro-MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human NOD1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the D-Glu and meso-DAP in the peptide stem strongly reduced hNOD1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human NOD1 and Nod2 stimulatory capabilities.
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NOD1 and nod2 signaling host defense and inflammatory disease
Immunity, 2014Co-Authors: Roberta Caruso, Naohiro Inohara, Neil Warner, Gabriel NunezAbstract:The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
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characterization of natural human nucleotide binding oligomerization domain protein 1 NOD1 ligands from bacterial culture supernatant for elucidation of immune modulators in the environment
Journal of Biological Chemistry, 2010Co-Authors: Ambara R Pradipta, Naohiro Inohara, Mizuho Hasegawa, Yukari Fujimoto, Koichi FukaseAbstract:Abstract Nucleotide-binding oligomerization domain protein 1 (NOD1) is an intracellular protein that is involved in recognition of the bacterial component peptidoglycan. This recognition event induces a host defense response to eliminate invading pathogens. The genetic variation of NOD1 has been linked to several inflammatory diseases and allergies that are strongly affected by environmental factors. We have found that many bacteria having DAP-type peptidoglycan release NOD1 ligands into the environment. However, the structures of natural NOD1 ligands in the environment are not well understood. Herein we report the isolation and structural elucidation of natural human NOD1 (hNOD1) ligands from the Escherichia coli (E. coli) K-12 culture supernatant. The supernatant was fractionated with reverse phase HPLC, resulting in the isolation of several hNOD1 stimulatory fractions. Structural characterization studies demonstrated that the molecular structure of the most active fraction was the native hNOD1 ligand GlcNAc-(β1-4)-(anhydro)MurNAc-L-Ala-γ-D-Glu-meso-DAP. We also found other peptidoglycan (PGN) fragments using the 7-(diethylamino)coumarin-3-carbonyl (DEAC) labeling method to enhance the sensitivity in mass spectroscopy studies. These results suggested that DAP-containing bacteria release certain hNOD1 ligands to the environment, and these ligands would accumulate in the environment and regulate the immune system through NOD1.
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the cytosolic sensors NOD1 and nod2 are critical for bacterial recognition and host defense after exposure to toll like receptor ligands
Immunity, 2008Co-Authors: Yun Gi Kim, Naohiro Inohara, Jong Hwan Park, Michael H Shaw, Luigi Franchi, Gabriel NunezAbstract:Summary The cytosolic sensors NOD1 and Nod2 and Toll-like receptors (TLRs) activate defense signaling pathways in response to microbial stimuli. However, the role of NOD1 and Nod2 and their interplay with TLRs during systemic bacterial infection remains poorly understood. Here, we report that macrophages or mice made insensitive to TLRs by previous exposure to microbial ligands remained responsive to NOD1 and Nod2 stimulation. Furthermore, NOD1- and Nod2-mediated signaling and gene expression are enhanced in TLR-tolerant macrophages. Further analyses revealed that innate immune responses induced by bacterial infection relied on NOD1 and Nod2 and their adaptor RICK in macrophages pretreated with TLR ligands but not in naive macrophages. In addition, bacterial clearance upon systemic infection with L. monocytogenes was critically dependent on NOD1 and Nod2 when mice were previously stimulated with lipopolysaccharide or E. coli . Thus, NOD1 and Nod2 are important for microbial recognition and host defense after TLR stimulation.
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RICK/RIP2 mediates innate immune responses induced through NOD1 and Nod2 but not TLRs.
Journal of Immunology, 2007Co-Authors: Jong Hwan Park, Naohiro Inohara, Christine Mcdonald, Yun Gi Kim, Mizuho Hasegawa, Thirumala-devi Kanneganti, Mathilde Body-malapel, Gabriel NunezAbstract:RICK is a kinase that has been implicated in NOD1 and Nod2 signaling. In addition, RICK has been proposed to mediate TLR signaling in that its absence confers reduced responses to certain bacterial products such as LPS. We show here that macrophages and mice lacking RICK are defective in their responses to NOD1 and Nod2 agonists but exhibit unimpaired responses to synthetic and highly purified TLR agonists. Furthermore, production of chemokines induced by the bacterial dipeptide gamma-d-glutamyl-meso-diaminopimelic acid was intact in MyD88 deficient mice but abolished in RICK-null mice. Stimulation of macrophages with muramyl dipeptide, the Nod2 activator, enhanced immune responses induced by LPS, IFN-gamma, and heat-killed Listeria in wild-type but not in RICK- or Nod2-deficient macrophages. Finally, we show that the absence of RICK or double deficiency of NOD1 and Nod2 was associated with reduced cytokine production in Listeria-infected macrophages. These results demonstrate that RICK functions in innate immunity by mediating NOD1 and Nod2 signaling but not TLR-mediated immune responses.
Jong Hwan Park - One of the best experts on this subject based on the ideXlab platform.
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Activation of NOD1 and Nod2 induces innate immune responses of prostate epithelial cells.
The Prostate, 2012Co-Authors: Min-jung Kang, Dongjae Kim, Sook-kyoung Heo, Eun-jung Song, Seung-yun Han, Ju-hee Han, Bo Yeon Kim, Jong Hwan ParkAbstract:BACKGROUND. NOD1 and Nod2 are cytosolic receptors which are responsible for sensing bacterial peptidoglycan derivatives. In this study, we determined whether NOD1 and Nod2 are involved in the innate immune responses of prostate epithelial cells. METHODS. The expression of NOD1 and Nod2 was examined by RT-PCR and immunohistochemistry. ELISA was performed to determine the production of cytokines/chemokines. Activation of NF-kB and MAPK was examined using western blot analysis. RESULTS. The NOD1 gene was distinctly expressed in all tested cells including DU145, PC3, and TRAMP-C2 cells, whereas Nod2 expression was weak. Both NOD1 and Nod2 proteins were expressed in normal mouse prostate epithelia with difference of expression levels. TriDAP (NOD1 agonist), but not MDP (Nod2), increased the production of IL-8 (or KC) and IL-6 in prostate epithelial cells. Tri-DAP and MDP could upregulate the gene expression of COX-2 and activate NF-kB and MAPK. In addition, Tri-DAP and MDP synergized with TLR agonists to induce the production of IL-8/KC or IL-6 in PC3 and TRAMP-C2 cells. We finally showed that NOD1 and Nod2 were also expressed in a wide range of prostate lesions including prostate intraepithelial neoplasm (PIN), phyllodes-like tumor, and adenocarcinoma in TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, even though the expression level of NOD1 and Nod2 was different. CONCLUSION. These results indicate that NOD1 and Nod2 may play important roles in the innate immune response of prostate epithelial cells and the development and progression of prostate cancer. Prostate 72:1351–1358, 2012. # 2012 Wiley Periodicals, Inc.
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viral infection augments NOD1 2 signaling to potentiate lethality associated with secondary bacterial infections
Cell Host & Microbe, 2011Co-Authors: Yun Gi Kim, Jong Hwan Park, Thornik Reimer, Darren P Baker, Taro Kawai, Himanshu Kumar, Shizuo Akira, Christiane E Wobus, Gabriel NunezAbstract:Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs NOD1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced NOD1 and Nod2 signaling by poly I:C required the TLR3/MDA5 adaptors TRIF and IPS-1 and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-β induced the expression of NOD1, Nod2, and the Nod-signaling adaptor Rip2. Systemic administration of poly I:C or IFN-β or infection with murine norovirus-1 promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden but attenuated in the absence of NOD1/Nod2 or Rip2. Thus, crosstalk between type I IFNs and NOD1/Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.
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implication of NOD1 and nod2 for the differentiation of multipotent mesenchymal stem cells derived from human umbilical cord blood
PLOS ONE, 2010Co-Authors: Hyung Sik Kim, Jong Hwan Park, Taehoon Shin, Seran Yang, Minsoo Seo, Dongjae Kim, Sookyung Kang, Kyungsun KangAbstract:Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are known to trigger an innate immune response against microbial infection. Although studies suggest that activation of TLRs modulate the function of mesenchymal stem cells (MSCs), little is known about the role of NLRs on the MSC function. In this study, we investigated whether NOD1 and NOD2 regulate the functions of human umbilical cord blood-derived MSCs (hUCB-MSCs). The genes of TLR2, TLR4, NOD1, and NOD2 were expressed in hUCB-MSCs. Stimulation with each agonist (Pam3CSK4 for TLR2, LPS for TLR4, Tri-DAP for NOD1, and MDP for NOD2) led to IL-8 production in hUCB-MSC, suggesting the expressed receptors are functional in hUCB-MSC. CCK-8 assay revealed that none of agonist influenced proliferation of hUCB-MSCs. We next examined whether TLR and NLR agonists affect osteogenic-, adipogenic-, and chondrogenic differentiation of hUCB-MSCs. Pam3CSK4 and Tri-DAP strongly enhanced osteogenic differentiation and ERK phosphorylation in hUCB-MSCs, and LPS and MDP also slightly did. Treatment of U0126 (MEK1/2 inhibitor) restored osteogenic differentiation enhanced by Pam3CSK4. Tri-DAP and MDP inhibited adipogenic differentiation of hUCB-MSCs, but Pam3CSK4 and LPS did not. On chondrogenic differentiation, all TLR and NLR agonists could promote chondrogenesis of hUCB-MSCs with difference in the ability. Our findings suggest that NOD1 and NOD2 as well as TLRs are involved in regulating the differentiation of MSCs.
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Cross-tolerization between NOD1 and Nod2 signaling results in reduced refractoriness to bacterial infection in Nod2-deficient macrophages.
The Journal of Immunology, 2008Co-Authors: Yun Gi Kim, Jong Hwan Park, Stephanie Daignault, Koichi Fukase, Gabriel NunezAbstract:Nod2 is an intracellular innate immune receptor that plays a role in host defense and susceptibility to inflammatory disease. We show in this study that macrophages rendered refractory to TLR4 and Nod2 signaling by exposure to LPS and muramyl dipeptide (MDP) exhibit impaired TNF-alpha and IL-6 production in response to pathogenic Listeria monocytogenes and Yersinia pseudotuberculosis as well as commensal bacteria including Escherichia coli and Bacteroides fragilis. Surprisingly, Nod2 deficiency was associated with impaired tolerization in response to pathogenic and commensal bacteria. Mechanistically, reduced tolerization of Nod2-null macrophages was mediated by recognition of bacteria through NOD1 because it was abolished in macrophages deficient in NOD1 and Nod2. Consistently, Nod2-null macrophages tolerant to LPS and MDP showed enhanced production of TNF-alpha and IL-6 as well as increased NF-kappaB and MAPK activation in response to the dipeptide KF1B, the NOD1 agonist. Furthermore, reduced tolerization of Nod2-deficient macrophages in response to bacteria was abolished when mutant macrophages were also rendered tolerant to the NOD1 ligand. Finally, MDP stimulation induced refractoriness not only to MDP, but also to iE-DAP stimulation, providing a mechanism to explain the reduced tolerization of Nod2-deficient macrophages infected with bacteria. These results demonstrate that cross-tolerization between NOD1 and Nod2 leads to increase recognition of both pathogenic and commensal bacteria in Nod2-deficient macrophages pre-exposed to microbial ligands.
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the cytosolic sensors NOD1 and nod2 are critical for bacterial recognition and host defense after exposure to toll like receptor ligands
Immunity, 2008Co-Authors: Yun Gi Kim, Naohiro Inohara, Jong Hwan Park, Michael H Shaw, Luigi Franchi, Gabriel NunezAbstract:Summary The cytosolic sensors NOD1 and Nod2 and Toll-like receptors (TLRs) activate defense signaling pathways in response to microbial stimuli. However, the role of NOD1 and Nod2 and their interplay with TLRs during systemic bacterial infection remains poorly understood. Here, we report that macrophages or mice made insensitive to TLRs by previous exposure to microbial ligands remained responsive to NOD1 and Nod2 stimulation. Furthermore, NOD1- and Nod2-mediated signaling and gene expression are enhanced in TLR-tolerant macrophages. Further analyses revealed that innate immune responses induced by bacterial infection relied on NOD1 and Nod2 and their adaptor RICK in macrophages pretreated with TLR ligands but not in naive macrophages. In addition, bacterial clearance upon systemic infection with L. monocytogenes was critically dependent on NOD1 and Nod2 when mice were previously stimulated with lipopolysaccharide or E. coli . Thus, NOD1 and Nod2 are important for microbial recognition and host defense after TLR stimulation.
