The Experts below are selected from a list of 58119 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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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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Dectin-1 and NOD2 mediate cathepsin activation in zymosan-induced arthritis in mice
Inflammation Research, 2011Co-Authors: Holly L Rosenzweig, James T. Rosenbaum, Gabriel Nunez, Jenna S. Clowers, Michael P. DaveyAbstract:Objective Activation of pattern recognition receptors (PRR) may contribute to arthritis. Here, we elucidated the role of NOD2, a genetic cause of inflammatory arthritis, and several other PRR in a murine model of inflammatory arthritis. Methods The roles of CR3, TLR2, MyD88, NOD1, NOD2, Dectin-1 and Dectin-2 were tested in vivo in arthritis elicited by intra-articular injections of zymosan, the fungal cell wall components curdlan, laminarin and mannan, and the bacterial cell wall peptidoglycan. Results Dectin-1, and to a lesser extent Dectin-2, contributed to arthritis. TLR2, MyD88 and CR3 played non-essential roles. Observations based on injection of curdlan, laminarin or mannan supported the dominant role of the Dectin-1 pathway in the joint. We demonstrated differential roles for NOD1 and NOD2 and identified NOD2 as a novel and essential mediator of zymosan-induced arthritis. Conclusions Together, Dectin-1 and NOD2 are critical, sentinel receptors in the arthritogenic effects of zymosan. Our data identify a novel role for NOD2 during inflammatory responses within joints.
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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.
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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.
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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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.
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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 Bodymalapel, 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.
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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new role of nod proteins in regulation of intestinal goblet cell response in the context of innate host defense in an enteric parasite infection
Infection and Immunity, 2016Co-Authors: Huaqing Wang, Janice J Kim, Emmanuel Denou, Amanda L Gallagher, David J Thornton, Sharif M Shajib, Lijun Xia, Jonathan D Schertzer, Richard K Grencis, Dana J. PhilpottAbstract:Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite Trichuris muris. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and NOD2 double-knockout (Nod DKO) mice after T. muris infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and NOD2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or NOD2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and NOD2 agonists upregulated core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS-stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and NOD2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense.
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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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the protein atg16l1 suppresses inflammatory cytokines induced by the intracellular sensors nod1 and NOD2 in an autophagy independent manner
Immunity, 2013Co-Authors: Matthew T. Sorbara, Leonardo H. Travassos, Stephen E. Girardin, Mahendrasingh Ramjeet, Lisa K Ellison, Nicola L Jones, Dana J. PhilpottAbstract:The peptidoglycan sensor NOD2 and the autophagy protein ATG16L1 have been linked to Crohn's disease (CD). Although NOD2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or NOD2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.
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nod1 and NOD2 signaling does not alter the composition of intestinal bacterial communities at homeostasis
Gut microbes, 2013Co-Authors: Susan J. Robertson, Stephen E. Girardin, Stephen Rubino, Jun Yu Zhou, Kaoru Geddes, Joon Ho Cho, Dana J. PhilpottAbstract:Patients with inflammatory bowel diseases (IBD) harbour intestinal bacterial communities with altered composition compared with healthy counterparts; however, it is unknown whether changes in the microbiota are associated with genetic susceptibility of individuals for developing disease or instead reflect other changes in the intestinal environment related to the disease itself. Since deficiencies in the innate immune receptors Nod1 and NOD2 are linked to IBD, we tested the hypothesis that Nod-signaling alters intestinal immune profiles and subsequently alters bacterial community structure. We used qPCR to analyze expression patterns of selected immune mediators in the ileum and cecum of Nod-deficient mice compared with their Nod-sufficient littermates and assessed the relative abundance of major bacterial groups sampled from the ileum, cecum and colon. The Nod1-deficient ileum exhibited significantly lower expression of NOD2, Muc2, α- and β-defensins and keratinocyte-derived chemokine (KC), suggesting a weakened epithelial barrier compared with WT littermates; however, there were no significant differences in the relative abundance of targeted bacterial groups, indicating that Nod1-associated immune differences alone do not promote dysbiosis. Furthermore, NOD2-deficient mice did not display any changes in the expression of immune markers or bacterial communities. Shifts in bacterial communities that were observed in this study correlated with housing conditions and were independent of genotype. These findings emphasize the importance of using F2 littermate controls to minimize environmental sources of variation in microbial analyses, to establish baseline conditions for host-microbe homeostasis in Nod-deficient mice and to strengthen models for testing factors contributing to microbial dysbiosis associated with IBD.
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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the protein atg16l1 suppresses inflammatory cytokines induced by the intracellular sensors nod1 and NOD2 in an autophagy independent manner
Immunity, 2013Co-Authors: Matthew T. Sorbara, Leonardo H. Travassos, Stephen E. Girardin, Mahendrasingh Ramjeet, Lisa K Ellison, Nicola L Jones, Dana J. PhilpottAbstract:The peptidoglycan sensor NOD2 and the autophagy protein ATG16L1 have been linked to Crohn's disease (CD). Although NOD2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or NOD2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.
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nod1 and NOD2 signaling does not alter the composition of intestinal bacterial communities at homeostasis
Gut microbes, 2013Co-Authors: Susan J. Robertson, Stephen E. Girardin, Stephen Rubino, Jun Yu Zhou, Kaoru Geddes, Joon Ho Cho, Dana J. PhilpottAbstract:Patients with inflammatory bowel diseases (IBD) harbour intestinal bacterial communities with altered composition compared with healthy counterparts; however, it is unknown whether changes in the microbiota are associated with genetic susceptibility of individuals for developing disease or instead reflect other changes in the intestinal environment related to the disease itself. Since deficiencies in the innate immune receptors Nod1 and NOD2 are linked to IBD, we tested the hypothesis that Nod-signaling alters intestinal immune profiles and subsequently alters bacterial community structure. We used qPCR to analyze expression patterns of selected immune mediators in the ileum and cecum of Nod-deficient mice compared with their Nod-sufficient littermates and assessed the relative abundance of major bacterial groups sampled from the ileum, cecum and colon. The Nod1-deficient ileum exhibited significantly lower expression of NOD2, Muc2, α- and β-defensins and keratinocyte-derived chemokine (KC), suggesting a weakened epithelial barrier compared with WT littermates; however, there were no significant differences in the relative abundance of targeted bacterial groups, indicating that Nod1-associated immune differences alone do not promote dysbiosis. Furthermore, NOD2-deficient mice did not display any changes in the expression of immune markers or bacterial communities. Shifts in bacterial communities that were observed in this study correlated with housing conditions and were independent of genotype. These findings emphasize the importance of using F2 littermate controls to minimize environmental sources of variation in microbial analyses, to establish baseline conditions for host-microbe homeostasis in Nod-deficient mice and to strengthen models for testing factors contributing to microbial dysbiosis associated with IBD.
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ph dependent internalization of muramyl peptides from early endosomes enables nod1 and NOD2 signaling
Journal of Biological Chemistry, 2009Co-Authors: Jooeun Lee, Dana J. Philpott, Stephan R. Vavricka, Ivan Tattoli, Kacper A Wojtal, Stephen E. GirardinAbstract:Nod1 and NOD2 are members of the Nod-like receptor family that detect intracellular bacterial peptidoglycan-derived muramyl peptides. The biological effects of muramyl peptides have been described for over three decades, but the mechanism underlying their internalization to the cytosol remains unclear. Using the human epithelial cell line HEK293T as a model system, we demonstrate here that Nod1-activating ligands entered cells through endocytosis, most likely by the clathrin-coated pit pathway, as internalization was dynamin-dependent but not inhibited by methyl-beta-cyclodextrin. In the endocytic pathway, the cytosolic internalization of Nod1 ligands was pH-dependent, occurred prior to the acidification mediated by the vacuolar ATPase, and was optimal at pH ranging from 5.5 to 6. Similarly, the NOD2 ligand MDP was internalized into host cytosol through a similar pathway with optimal pH for internalization ranging from 5.5 to 6.5. Moreover, Nod1-activating muramyl peptides likely required processing by endosomal enzymes, prior to transport into the cytosol, suggesting the existence of a sterically gated endosomal transporter for Nod1 ligands. In support for this, we identified a role for SLC15A4, an oligopeptide transporter expressed in early endosomes, in Nod1-dependent NF-kappaB signaling. Interestingly, SLC15A4 expression was also up-regulated in colonic biopsies from patients with inflammatory bowel disease, a disorder associated with mutations in Nod1 and NOD2. Together, our results shed light on the mechanisms by which muramyl peptides get access to the host cytosol, where they are detected by Nod1 and NOD2, and might have implications for the understanding of human diseases, such as inflammatory bowel disease.
Yun Gi Kim - One of the best experts on this subject based on the ideXlab platform.
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nod1 and NOD2 direct autophagy by recruiting atg16l1 to the plasma membrane at the site of bacterial entry
Nature Immunology, 2010Co-Authors: Leonardo H. Travassos, Joao G Magalhaes, Yun Gi Kim, Leticia A M Carneiro, Mahendrasingh Ramjeet, Seamus Hussey, Linda Yuan, Fraser Soares, Evelyn Chea, Lionel Le BourhisAbstract:Autophagy facilitates host defense against invading bacteria. Philpott and colleagues show that Nod1 and NOD2 link pathogen sensing to autophagy by recruiting the autophagy protein AGT16L1 to the site of pathogen entry.
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nod1 and NOD2 direct autophagy by recruiting atg16l1 to the plasma membrane at the site of bacterial entry
Nature Immunology, 2010Co-Authors: Leonardo H. Travassos, Joao G Magalhaes, Yun Gi Kim, Leticia A M Carneiro, Mahendrasingh Ramjeet, Seamus Hussey, Linda Yuan, Fraser Soares, Evelyn Chea, Lionel Le BourhisAbstract:Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and NOD2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and NOD2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease-associated NOD2 frameshift mutation, mutant NOD2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between NOD2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.
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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.
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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.
