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• W2895834481 abstract "Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn’s disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development. Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn’s disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development. SummaryAlthough the association between Crohn’s disease susceptibility and nucleotide-binding oligomerization domain 2 polymorphisms was shown in 2001, the mechanisms involved remain largely unknown. In this review, we report the role of nucleotide-binding oligomerization domain 2 in epithelial cells in the development of colitis and associated carcinogenesis. Although the association between Crohn’s disease susceptibility and nucleotide-binding oligomerization domain 2 polymorphisms was shown in 2001, the mechanisms involved remain largely unknown. In this review, we report the role of nucleotide-binding oligomerization domain 2 in epithelial cells in the development of colitis and associated carcinogenesis. The gastrointestinal mucosa constitutes the largest interface of the human body between the external environment and the organism interior milieu. It establishes a dynamic barrier that excludes potentially harmful compounds (microbes, toxic ingested molecules) present in the intestinal lumen, while permitting sampling and absorption of the luminal content.1Jung C. Hugot J.P. Barreau F. Peyer's patches: the immune sensors of the intestine.Int J Inflam. 2010; 2010: 823710Crossref PubMed Google Scholar To maintain this barrier, it is necessary to renew the gut epithelium continuously. The surface of the intestine is composed of a columnar epithelial mucosa, within which the crypts are located. At the base of the crypts are the intestinal stem cells, ensuring the renewal of the epithelial lining by proliferating, giving rise to progenitor cells that differentiate into the 7 specialized lineages composing the intestinal epithelium: enterocytes, which represent the large majority of the epithelial cell population and allow absorption of nutrients and water; goblet cells, which secrete mucus as a protective barrier; Paneth cells, which are present only in the small intestine crypts, and secrete antimicrobial peptides (AMPs) and paracrine molecules, which participate in the stem cell niche; enteroendocrine cells, which secrete hormones; the newly identified tuft cells, which are thought to secrete prostaglandin precursors, with immunologic functions and interacting with the gut nervous system2Gerbe F. Legraverend C. Jay P. The intestinal epithelium tuft cells: specification and function.Cell Mol Life Sci. 2012; 69: 2907-2917Crossref PubMed Scopus (178) Google Scholar; M cells (microfold cells), which have a pivotal role in antigen presentation from the luminal content to immune cells1Jung C. Hugot J.P. Barreau F. Peyer's patches: the immune sensors of the intestine.Int J Inflam. 2010; 2010: 823710Crossref PubMed Google Scholar; and, finally, cup cells, which are involved in the induction of immune response to luminal bacteria.3Madara J.L. Carlson S.L. Cup cells: further structural characterization of the brush border and the suggestion that they may serve as an attachment site for an unidentified bacillus in guinea pig ileum.Gastroenterology. 1985; 89: 1374-1386Abstract Full Text PDF PubMed Scopus (12) Google Scholar In the intestinal mucosa, these different cell types interact together to form a continuous epithelium, isolating the luminal content from the internal milieu.4Barreau F. Hugot J. Intestinal barrier dysfunction triggered by invasive bacteria.Curr Opin Microbiol. 2014; 17C: 91-98Crossref Scopus (75) Google Scholar This physical barrier is reinforced by the presence of a mucus wall, including mucins and AMPs, made by a coordinated secretion from the intestinal cells. The last element of the intestinal barrier is achieved by the microbiota, which limits the pathogen invasion. In healthy people, interactions between the 3 compartments of the digestive mucosa, namely the immune system, the epithelial layer, and the microbiota, are characterized by a homeostatic state. A very large panel of human diseases, including burns, sepsis, inflammatory bowel disease, celiac disease, irritable bowel syndrome, intestinal ischemia, graft-versus-host disease, cirrhosis, graft rejection after small-bowel transplantation, food intolerance, allergy, malnutrition, rheumatoid arthritis, obesity, diabetes, and colorectal cancer, are linked to a loss of gut barrier homeostasis. The nucleotide-binding oligomerization domain containing 2 (NOD2, also known as caspase activation and recruitment domain [CARD]15 and Nod-like receptor-C2) gene is a member of the evolutionarily conserved Nod-like receptors family, which sense components of the microbial cell wall. In the past decade, numerous studies have reported that Nod2 plays a pivotal role in the regulation of chronic inflammatory conditions.5Al Nabhani Z. Dietrich G. Hugot J.P. Barreau F. Nod2: the intestinal gate keeper.PLoS Pathog. 2017; 13: e1006177Crossref PubMed Scopus (89) Google Scholar NOD2 polymorphisms were found to be associated with an increased risk of Crohn’s disease (CD)6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4675) Google Scholar and colorectal cancer (CRC)7Kurzawski G. Suchy J. Kladny J. Grabowska E. Mierzejewski M. Jakubowska A. Debniak T. Cybulski C. Kowalska E. Szych Z. Domagala W. Scott R.J. Lubinski J. The NOD2 3020insC mutation and the risk of colorectal cancer.Cancer Res. 2004; 64: 1604-1606Crossref PubMed Scopus (94) Google Scholar since 2001 and 2004, respectively. The most commonly studied polymorphisms includes 2 missense mutations and a frameshift mutation, located within coding regions and affecting the function of NOD2 by altering its amino acid sequence. Although an abundant amount of literature since then has mainly confirmed the link between NOD2 polymorphisms and CD susceptibility, its association with different cancers, including gastric, colorectal, endometrial, breast, ovarian, and laryngeal, remains unclear by a lack of consensus between the different studies reported. Nevertheless, a recent meta-analysis has shown that NOD2 rs2066844 C/T, rs2066845 C/G, and rs2066847 (3020insC) polymorphisms are associated with an increased cancer risk, especially in regard to gastrointestinal cancer.8Liu J. He C. Xu Q. Xing C. Yuan Y. NOD2 polymorphisms associated with cancer risk: a meta-analysis.PLoS One. 2014; 9: e89340Crossref PubMed Scopus (36) Google Scholar In the intestine, NOD2 is expressed by both hematopoietic9Penack O. Smith O.M. Cunningham-Bussel A. Liu X. Rao U. Yim N. Na I.K. Holland A.M. Ghosh A. Lu S.X. Jenq R.R. Liu C. Murphy G.F. Brandl K. van den Brink M.R. NOD2 regulates hematopoietic cell function during graft-versus-host disease.J Exp Med. 2009; 206: 2101-2110Crossref PubMed Scopus (88) Google Scholar and nonhematopoietic cells forming the intestinal epithelium.10Ogura Y. Lala S. Xin W. Smith E. Dowds T.A. Chen F.F. Zimmermann E. Tretiakova M. Cho J.H. Hart J. Greenson J.K. Keshav S. Nunez G. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis.Gut. 2003; 52: 1591-1597Crossref PubMed Scopus (372) Google Scholar, 11Nigro G. Rossi R. Commere P.H. Jay P. Sansonetti P.J. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration.Cell Host Microbe. 2014; 15: 792-798Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 12Ramanan D. Tang M.S. Bowcutt R. Loke P. Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.Immunity. 2014; 41: 311-324Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 13Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar NOD2 senses the muramyl dipeptide (MDP), which arises from the partial degradation of a bacterial component (peptidoglycan).15Girardin S.E. Boneca I.G. Viala J. Chamaillard M. Labigne A. Thomas G. Philpott D.J. Sansonetti P.J. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.J Biol Chem. 2003; 278: 8869-8872Crossref PubMed Scopus (1906) Google Scholar After stimulation by MDP, NOD2 promotes host defense through the production of cytokines,16Alnabhani Z. Montcuquet N. Biaggini K. Dussaillant M. Roy M. Ogier-Denis E. Madi A. Jallane A. Feuilloley M. Hugot J.P. Connil N. Barreau F. Pseudomonas fluorescens alters the intestinal barrier function by modulating IL-1beta expression through hematopoietic NOD2 signaling.Inflamm Bowel Dis. 2015; 21: 543-555Crossref PubMed Scopus (18) Google Scholar, 17Meinzer U. Barreau F. Esmiol-Welterlin S. Jung C. Villard C. Leger T. Ben-Mkaddem S. Berrebi D. Dussaillant M. Alnabhani Z. Roy M. Bonacorsi S. Wolf-Watz H. Perroy J. Ollendorff V. Hugot J.P. Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1 pathway and activates caspase-1 to induce intestinal barrier dysfunction.Cell Host Microbe. 2012; 11: 337-351Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar chemokines,16Alnabhani Z. Montcuquet N. Biaggini K. Dussaillant M. Roy M. Ogier-Denis E. Madi A. Jallane A. Feuilloley M. Hugot J.P. Connil N. Barreau F. Pseudomonas fluorescens alters the intestinal barrier function by modulating IL-1beta expression through hematopoietic NOD2 signaling.Inflamm Bowel Dis. 2015; 21: 543-555Crossref PubMed Scopus (18) Google Scholar AMPs,18Kobayashi K.S. Chamaillard M. Ogura Y. Henegariu O. Inohara N. Nunez G. Flavell R.A. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.Science. 2005; 307: 731-734Crossref PubMed Scopus (1471) Google Scholar mucins,12Ramanan D. Tang M.S. Bowcutt R. Loke P. Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.Immunity. 2014; 41: 311-324Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar and activation of both innate and adaptive immune responses. Under basal conditions, NOD2 protein, which has 3 domains including CARDs, NACHT (or NOD), and leucine-rich repeats (Figure 1), is auto-inhibited through the interaction between its different domains. The chaperone protein heat shock protein 90 is involved in this phenomenon.19Boyle J.P. Parkhouse R. Monie T.P. Insights into the molecular basis of the NOD2 signalling pathway.Open Biol. 2014; 4Crossref PubMed Scopus (72) Google Scholar MDP interacts directly with the leucine-rich repeat domain, allowing activation of the NACHT domain and the interaction of the CARD domains with other CARD-containing proteins (Figure 1). As a result, activation of NOD2 by MDP triggers oligomerization of the receptors via their NOD domains and the recruitment of mediators needed to form a signaling complex named nodosome,20Tattoli I. Travassos L.H. Carneiro L.A. Magalhaes J.G. Girardin S.E. The Nodosome: Nod1 and Nod2 control bacterial infections and inflammation.Semin Immunopathol. 2007; 29: 289-301Crossref PubMed Scopus (94) Google Scholar enhancing nuclear factor-κB (NF-κB) and mitogen activated protein kinase (MAPK) pathways.21Zhong Y. Kinio A. Saleh M. Functions of NOD-like receptors in human diseases.Front Immunol. 2013; 4: 333Crossref PubMed Google Scholar, 22Opitz B. Puschel A. Schmeck B. Hocke A.C. Rosseau S. Hammerschmidt S. Schumann R.R. Suttorp N. Hippenstiel S. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae.J Biol Chem. 2004; 279: 36426-36432Crossref PubMed Scopus (279) Google Scholar, 23Theivanthiran B. Batra S. Balamayooran G. Cai S. Kobayashi K. Flavell R.A. Jeyaseelan S. NOD2 signaling contributes to host defense in the lungs against Escherichia coli infection.Infect Immun. 2012; 80: 2558-2569Crossref PubMed Scopus (28) Google Scholar Since the discovery of its association with CD and CRC, the role of NOD2 in epithelial cells and immune cells has been studied extensively. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells to control the inflammatory process and the linked carcinogenesis development. The integrity of the intestinal epithelium is maintained by the continual renewal of epithelial cells as a result of the accelerated division of crypt cells that migrate upward from the base of the crypts. Today, although NOD2 is known to be expressed by epithelial enterocytes,13Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar goblet cells,12Ramanan D. Tang M.S. Bowcutt R. Loke P. Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.Immunity. 2014; 41: 311-324Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar Paneth cells,10Ogura Y. Lala S. Xin W. Smith E. Dowds T.A. Chen F.F. Zimmermann E. Tretiakova M. Cho J.H. Hart J. Greenson J.K. Keshav S. Nunez G. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis.Gut. 2003; 52: 1591-1597Crossref PubMed Scopus (372) Google Scholar and intestinal stem cells,11Nigro G. Rossi R. Commere P.H. Jay P. Sansonetti P.J. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration.Cell Host Microbe. 2014; 15: 792-798Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar no information is available concerning enteroendocrine, tuft, cup, and M cells. The highest expression of NOD2 has been reported in Paneth cells and intestinal stem cells. This probably explains why it initially was described that crypt epithelial cells express approximately 85-fold more NOD2 messenger RNA (mRNA) than villus epithelial cells.24Lala S. Ogura Y. Osborne C. Hor S.Y. Bromfield A. Davies S. Ogunbiyi O. Nunez G. Keshav S. Crohn's disease and the NOD2 gene: a role for Paneth cells.Gastroenterology. 2003; 125: 47-57Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar However, no data are available regarding the level of NOD2 expression in human small vs large intestine. Enterocytes are the most numerous cells of the intestinal mucosa (Figure 2A). Although their main roles are to ensure the absorption of nutrients and water, they also have the ability to synthesize AMPs, cytokines, and chemokines to control the stability of the microbiota and to induce the immune response. Finally, by their abilities to form a ring of tight junctions at the apical side of cells, enterocyte cells play an important role in the regulation of the gut paracellular permeability. Since 2003, we have known that enterocyte cells express NOD2 mRNA and protein in human colonic carcinoma epithelial cell lines and primary intestinal epithelial cells.13Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar After tumor necrosis factor-α (TNF-α) or interferon-γ (IFN-γ) stimulation, NOD2 mRNA and protein levels are increased in human colonic carcinoma.13Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar Moreover, a synergism between TNF-α and IFN-γ strongly enhances NOD2 expression.14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar This NOD2 overexpression is mediated by the NF-κB pathway.14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar Two NF-κB binding sites are identified in the promoter of NOD2. The deletion of either site, or the overexpression of a NF-κB dominant negative, leads to reduced levels of TNF-α/IFN-γ.14Rosenstiel P. Fantini M. Brautigam K. Kuhbacher T. Waetzig G.H. Seegert D. Schreiber S. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.Gastroenterology. 2003; 124: 1001-1009Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar Furthermore, this increased expression of NOD2 is associated with a reduced number of viable internalized Salmonella typhimurium in human epithelial cell lines compared with epithelial cells weakly expressing NOD2.13Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar In the context of Campylobacter jejuni infection, only Nod2knockout (KO) mice show a higher intestinal commensal Escherichia coli load associated with higher levels of IL6, TNF-α, and IL18, and a reduced IL22 level. This excessive immune response is probably owing to a reduced number of proliferating cells involved in the renewal of the intestinal epithelium.25Bereswill S. Grundmann U. Alutis M.E. Fischer A. Kuhl A.A. Heimesaat M.M. Immune responses upon Campylobacter jejuni infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2.Gut Pathog. 2017; 9: 33Crossref PubMed Scopus (4) Google Scholar Because Nod2 expression is inducible upon stimulation with bacterial products such as lipopolysaccharide,26Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nunez G. Fernandez-Luna J.L. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation.J Biol Chem. 2002; 277: 41701-41705Crossref PubMed Scopus (396) Google Scholar or after colonization of GF mice,27Petnicki-Ocwieja T. Hrncir T. Liu Y.J. Biswas A. Hudcovic T. Tlaskalova-Hogenova H. Kobayashi K.S. Nod2 is required for the regulation of commensal microbiota in the intestine.Proc Natl Acad Sci U S A. 2009; 106: 15813-15818Crossref PubMed Scopus (444) Google Scholar it is possible that Nod2 expression might be induced by the simple contact of epithelial intestinal cells with nonpathogenic commensal bacterium as E coli K12. Indeed, in vitro analyses have shown that the simple contact with E coli K12 is sufficient to induce Nod2 mRNA and protein in human intestinal epithelial cells.28Begue B. Dumant C. Bambou J.C. Beaulieu J.F. Chamaillard M. Hugot J.P. Goulet O. Schmitz J. Philpott D.J. Cerf-Bensussan N. Ruemmele F.M. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop.J Cell Physiol. 2006; 209: 241-252Crossref PubMed Scopus (52) Google Scholar However, this induction is not observed in human intestinal epithelial cells transfected with a plasmid encoding dominant-negative Toll-like receptor (TLR)-5. Furthermore, flagellin-negative E coli mutants failed to induce Nod2.28Begue B. Dumant C. Bambou J.C. Beaulieu J.F. Chamaillard M. Hugot J.P. Goulet O. Schmitz J. Philpott D.J. Cerf-Bensussan N. Ruemmele F.M. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop.J Cell Physiol. 2006; 209: 241-252Crossref PubMed Scopus (52) Google Scholar Moreover, microbial metabolites such as butyrate allow the up-regulation of the NOD2 expression in the intestinal epithelial cells.29Leung C.H. Lam W. Ma D.L. Gullen E.A. Cheng Y.C. Butyrate mediates nucleotide-binding and oligomerisation domain (NOD) 2-dependent mucosal immune responses against peptidoglycan.Eur J Immunol. 2009; 39: 3529-3537Crossref PubMed Scopus (44) Google Scholar Its expression in human colonic carcinoma cell line (T84) also is increased when cells are stimulated with a noninvasive E coli plus the hydrogen ionophore dinitrophenol, a disruptor of mitochondrial adenosine triphosphate synthesis.30Saxena A. Lopes F. Poon K.K.H. McKay D.M. Absence of the NOD2 protein renders epithelia more susceptible to barrier dysfunction due to mitochondrial dysfunction.Am J Physiol Gastrointest Liver Physiol. 2017; 313: G26-G38Crossref PubMed Scopus (25) Google Scholar Furthermore, an increased internalization of bacteria by epithelia presenting dysfunctional mitochondria (treated with dinitrophenol) is potentiated in NOD2-/- cells.30Saxena A. Lopes F. Poon K.K.H. McKay D.M. Absence of the NOD2 protein renders epithelia more susceptible to barrier dysfunction due to mitochondrial dysfunction.Am J Physiol Gastrointest Liver Physiol. 2017; 313: G26-G38Crossref PubMed Scopus (25) Google Scholar This uptake of bacteria is dependent on reactive oxygen species and MAPK, and the increased viable intracellular bacteria in NOD2-/- cells likely reflect a reduced ability to recognize and kill bacteria.30Saxena A. Lopes F. Poon K.K.H. McKay D.M. Absence of the NOD2 protein renders epithelia more susceptible to barrier dysfunction due to mitochondrial dysfunction.Am J Physiol Gastrointest Liver Physiol. 2017; 313: G26-G38Crossref PubMed Scopus (25) Google Scholar Collectively, these studies indicate that Nod2 expression in enterocytes is regulated by commensal bacteria or microbial components. The functional consequences of NOD2 stimulation by MDP are multiple. In response to MDP, intestinal epithelial cells synthesize and release at the apical side of AMPs such as C-C motif chemokine ligand 2028Begue B. Dumant C. Bambou J.C. Beaulieu J.F. Chamaillard M. Hugot J.P. Goulet O. Schmitz J. Philpott D.J. Cerf-Bensussan N. Ruemmele F.M. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop.J Cell Physiol. 2006; 209: 241-252Crossref PubMed Scopus (52) Google Scholar or human neutrophil peptide,31Yamamoto-Furusho J.K. Barnich N. Hisamatsu T. Podolsky D.K. MDP-NOD2 stimulation induces HNP-1 secretion, which contributes to NOD2 antibacterial function.Inflamm Bowel Dis. 2010; 16: 736-742Crossref PubMed Scopus (25) Google Scholar controlling the growth and/or survival of E coli and S typhimurium, respectively (Figure 1A). This AMP secretion is lost in NOD2 mutation (F3020insC) condition. MDP stimulation also induces secretion of chemokine (C-X-C motif) ligand-8 by intestinal epithelial cells, allowing the recruitment of neutrophils at the inflammatory site (Figure 1A). In the context of necrotizing enterocolitis, TLR-4 activation causes apoptosis in newborn intestine but not in adult mice.32Le Mandat Schultz A. Bonnard A. Barreau F. Aigrain Y. Pierre-Louis C. Berrebi D. Peuchmaur M. Expression of TLR-2, TLR-4, NOD2 and pNF-kappaB in a neonatal rat model of necrotizing enterocolitis.PLoS One. 2007; 2: e1102Crossref PubMed Scopus (58) Google Scholar TLR-4 expression and activation in intestinal epithelial cells are described to be influenced by NOD2.33Richardson W.M. Sodhi C.P. Russo A. Siggers R.H. Afrazi A. Gribar S.C. Neal M.D. Dai S. Prindle Jr., T. Branca M. Ma C. Ozolek J. Hackam D.J. Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium.Gastroenterology. 2010; 139 (17 e1-6): 904-917Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Indeed, NOD2 activation inhibits TLR-4 expression and activation in enterocytes, but not in macrophages, and reverses the effects of TLR-4 on intestinal mucosal injury and repair33Richardson W.M. Sodhi C.P. Russo A. Siggers R.H. Afrazi A. Gribar S.C. Neal M.D. Dai S. Prindle Jr., T. Branca M. Ma C. Ozolek J. Hackam D.J. Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium.Gastroenterology. 2010; 139 (17 e1-6): 904-917Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar (Figure 2A). Similar observations have been reported in the regulation of paracellular permeability of the intestinal mucosa, which is increased by TLR-2 or TLR-4 stimulations and normalized by Nod2 activation by MDP (Figure 3A).34Barreau F. Madre C. Meinzer U. Berrebi D. Dussaillant M. Merlin F. Eckmann L. Karin M. Sterkers G. Bonacorsi S. Lesuffleur T. Hugot J.P. Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches.Gut. 2010; 59: 207-217Crossref PubMed Scopus (77) Google Scholar In an inflammatory context, excessive levels of TNF-α and IFN-γ are reported to increase the intestinal paracellular permeability involving an enhanced long myosin light-chain kinase (MLCK) expression and activity.35Al Nabhani Z. Montcuquet N. Roy M. Dussaillant M. Hugot J.P. Barreau F. Complementary roles of Nod2 in hematopoietic and nonhematopoietic cells in preventing gut barrier dysfunction dependent on MLCK activity.Inflamm Bowel Dis. 2017; 23: 1109-1119Crossref PubMed Scopus (12) Google Scholar MLCK overexpression induced by TNF-α and IFN-γ is mediated by an increased expression of the TNF receptor (TNF-R) 2 receptor, triggering an induction of the NF-κB pathway35Al Nabhani Z. Montcuquet N. Roy M. Dussaillant M. Hugot J.P. Barreau F. Complementary roles of Nod2 in hematopoietic and nonhematopoietic cells in preventing gut barrier dysfunction dependent on MLCK activity.Inflamm Bowel Dis. 2017; 23: 1109-1119Crossref PubMed Scopus (12) Google Scholar (Figure 2A). TNF-α, through the TNF-R1 receptor, have been shown recently to also increase NOD2 expression.35Al Nabhani Z. Montcuquet N. Roy M. Dussaillant M. Hugot J.P. Barreau F. Complementary roles of Nod2 in hematopoietic and nonhematopoietic cells in preventing gut barrier dysfunction dependent on MLCK activity.Inflamm Bowel Dis. 2017; 23: 1109-1119Crossref PubMed Scopus (12) Google Scholar Then, activation of NOD2 by MDP is able to suppress the overexpression of MLCK (Figure 2A" @default.
• W2895834481 created "2018-10-26" @default.
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• W2895834481 date "2019-01-01" @default.
• W2895834481 modified "2023-10-16" @default.
• W2895834481 title "NOD2 Expression in Intestinal Epithelial Cells Protects Toward the Development of Inflammation and Associated Carcinogenesis" @default.
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