Korean J Physiol Pharmacol.  2015 Nov;19(6):479-484. 10.4196/kjpp.2015.19.6.479.

Role of Nucleotide-binding and Oligomerization Domain 2 Protein (NOD2) in the Development of Atherosclerosis

Affiliations
  • 1Department of Physiology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Tumor Heterogeneity and Network (THEN) Research Center, School of Medicine, Kyungpook National University, Daegu 41944, Korea. kimhajeong@knu.ac.kr

Abstract

NOD2 (nucleotide-binding and oligomerization domain 2) was initially reported as a susceptibility gene for Crohn's disease, with several studies focused on elucidating its molecular mechanism in the progression of Crohn's disease. We now know that NOD2 is an intracellular bacterial sensing receptor, and that MDP-mediated NOD2 activation drives inflammatory signaling. Various mutations in NOD2 have been reported, with NOD2 loss of function being associated with the development of Crohn's disease and other autoimmune diseases. These results suggest that NOD2 not only has an immune stimulatory function, but also an immune regulatory function. Atherosclerosis is a chronic inflammatory disease of the arterial wall; its pathologic progression is highly dependent on the immune balance. This immune balance is regulated by infiltrating monocytes and macrophages, both of which express NOD2. These findings indicate a potential role of NOD2 in atherosclerosis. The purpose of this review is to outline the known roles of NOD2 signaling in the pathogenesis of atherosclerosis.

Keyword

Atherosclerosis; Chronic inflammatory disease; Immune balance; NOD2

MeSH Terms

Atherosclerosis*
Autoimmune Diseases
Crohn Disease
Macrophages
Monocytes

Reference

1. Correa RG, Milutinovic S, Reed JC. Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases. Biosci Rep. 2012; 32:597–608. PMID: 22908883.
Article
2. Girardin SE, Travassos LH, Hervé M, Blanot D, Boneca IG, Philpott DJ, Sansonetti PJ, Mengin-Lecreulx D. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem. 2003; 278:41702–41708. PMID: 12871942.
Article
3. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem. 2001; 276:4812–4818. PMID: 11087742.
4. Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum. 2013; 43:125–130. PMID: 23352252.
Article
5. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014; 14:9–23. PMID: 24336102.
Article
6. Grimes CL, Ariyananda Lde Z, Melnyk JE, O'Shea EK. The innate immune protein Nod2 binds directly to MDP, a bacterial cell wall fragment. J Am Chem Soc. 2012; 134:13535–13537. PMID: 22857257.
Article
7. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology. 2003; 124:993–1000. PMID: 12671896.
Article
8. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003; 278:8869–8872. PMID: 12527755.
Article
9. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohns disease. Nature. 2001; 411:599–603. PMID: 11385576.
Article
10. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009; 361:2066–2078. PMID: 19923578.
Article
11. Yamamoto S, Ma X. Role of Nod2 in the development of Crohn's disease. Microbes Infect. 2009; 11:912–918. PMID: 19573617.
Article
12. Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013; 4:333. PMID: 24137163.
Article
13. Caruso R, Warner N, Inohara N, Núñez G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity. 2014; 41:898–908. PMID: 25526305.
Article
14. Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, OMorain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP. Epwg-Ibd Group. Epimad Group. Getaid Group. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002; 70:845–857. PMID: 11875755.
Article
15. Coulombe F, Divangahi M, Veyrier F, de Léséleuc L, Gleason JL, Yang Y, Kelliher MA, Pandey AK, Sassetti CM, Reed MB, Behr MA. Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med. 2009; 206:1709–1716. PMID: 19581406.
Article
16. Zhu K, Yin X, Tang X, Zhang F, Yang S, Zhang X. Meta-analysis of NOD2/CARD15 polymorphisms with psoriasis and psoriatic arthritis. Rheumatol Int. 2012; 32:1893–1900. PMID: 21448648.
Article
17. Liu HQ, Zhang XY, Edfeldt K, Nijhuis MO, Idborg H, Bäck M, Roy J, Hedin U, Jakobsson PJ, Laman JD, de Kleijn DP, Pasterkamp G, Hansson GK, Yan ZQ. NOD2-mediated innate immune signaling regulates the eicosanoids in atherosclerosis. Arterioscler Thromb Vasc Biol. 2013; 33:2193–2201. PMID: 23868940.
Article
18. Yuan H, Zelkha S, Burkatovskaya M, Gupte R, Leeman SE, Amar S. Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss. Proc Natl Acad Sci U S A. 2013; 110:E5059–E5068. PMID: 24324141.
Article
19. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006; 367:1747–1757. PMID: 16731270.
Article
20. Anogeianaki A, Angelucci D, Cianchetti E, D'Alessandro M, Maccauro G, Saggini A, Salini V, Caraffa A, Tete S, Conti F, Tripodi D, Shaik-Dasthagirisaheb YB. Atherosclerosis: a classic inflammatory disease. Int J Immunopathol Pharmacol. 2011; 24:817–825. PMID: 22230389.
Article
21. Theoharides TC, Sismanopoulos N, Delivanis DA, Zhang B, Hatziagelaki EE, Kalogeromitros D. Mast cells squeeze the heart and stretch the gird: their role in atherosclerosis and obesity. Trends Pharmacol Sci. 2011; 32:534–542. PMID: 21741097.
Article
22. Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol. 2009; 27:165–197. PMID: 19302038.
23. Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, Sukhova GK, Lee RT. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996; 7:330–335. PMID: 8937525.
Article
24. Epstein SE, Zhou YF, Zhu J. Potential role of cytomegalovirus in the pathogenesis of restenosis and atherosclerosis. Am Heart J. 1999; 138:S476–S478. PMID: 10539852.
Article
25. Saikku P. Chlamydia pneumoniae in atherosclerosis. J Intern Med. 2000; 247:391–396. PMID: 10762457.
Article
26. Laberge MA, Moore KJ, Freeman MW. Atherosclerosis and innate immune signaling. Ann Med. 2005; 37:130–140. PMID: 16026120.
Article
27. Zelkha SA, Freilich RW, Amar S. Periodontal innate immune mechanisms relevant to atherosclerosis and obesity. Periodontol 2000. 2010; 54:207–221. PMID: 20712641.
Article
28. Katz JT, Shannon RP. Bacteria and coronary atheroma: more fingerprints but no smoking gun. Circulation. 2006; 113:920–922. PMID: 16490832.
29. Andraws R, Berger JS, Brown DL. Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials. JAMA. 2005; 293:2641–2647. PMID: 15928286.
Article
30. Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, Patel S, Card DJ, Hermanowski-Vosatka A, Bergstrom JD, Sparrow CP, Detmers PA, Chao YS. Infectious agents are not necessary for murine atherogenesis. J Exp Med. 2000; 191:1437–1442. PMID: 10770809.
Article
31. Cole JE, Kassiteridi C, Monaco C. Toll-like receptors in atherosclerosis: a 'Pandora's box' of advances and controversies. Trends Pharmacol Sci. 2013; 34:629–636. PMID: 24139612.
Article
32. Deshmukh HS, Hamburger JB, Ahn SH, McCafferty DG, Yang SR, Fowler VG Jr. Critical role of NOD2 in regulating the immune response to Staphylococcus aureus. Infect Immun. 2009; 77:1376–1382. PMID: 19139201.
33. Shimada K, Chen S, Dempsey PW, Sorrentino R, Alsabeh R, Slepenkin AV, Peterson E, Doherty TM, Underhill D, Crother TR, Arditi M. The NOD/RIP2 pathway is essential for host defenses against Chlamydophila pneumoniae lung infection. PLoS Pathog. 2009; 5:e1000379. PMID: 19360122.
Article
34. Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, Sahly H, Lucius R, Fölsch UR, Philpott D, Schreiber S. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Cell Microbiol. 2006; 8:1188–1198. PMID: 16819970.
Article
35. Loving CL, Osorio M, Kim YG, Nuñez G, Hughes MA, Merkel TJ. Nod1/Nod2-mediated recognition plays a critical role in induction of adaptive immunity to anthrax after aerosol exposure. Infect Immun. 2009; 77:4529–4537. PMID: 19620350.
36. Laman JD, Schoneveld AH, Moll FL, van Meurs M, Pasterkamp G. Significance of peptidoglycan, a proinflammatory bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques. Am J Cardiol. 2002; 90:119–123. PMID: 12106839.
Article
37. Rubino SJ, Selvanantham T, Girardin SE, Philpott DJ. Nod-like receptors in the control of intestinal inflammation. Curr Opin Immunol. 2012; 24:398–404. PMID: 22677577.
Article
38. Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004; 5:800–808. PMID: 15220916.
Article
39. Kim H, Zhao Q, Zheng H, Li X, Zhang T, Ma X. A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation. Sci Rep. 2015; 5:12018. PMID: 26153766.
Article
40. Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Förster I, Kockx MM, Rajewsky K, Kraal G, Hofker MH, de Winther MP. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 112:1176–1185. PMID: 14561702.
41. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001; 19:683–765. PMID: 11244051.
Article
42. Noguchi E, Homma Y, Kang X, Netea MG, Ma X. A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol. 2009; 10:471–479. PMID: 19349988.
Article
43. Dagli N, Poyrazoglu OK, Dagli AF, Sahbaz F, Karaca I, Kobat MA, Bahcecioglu IH. Is inflammatory bowel disease a risk factor for early atherosclerosis? Angiology. 2010; 61:198–204. PMID: 19398421.
Article
44. Kayahan H, Sari I, Cullu N, Yuksel F, Demir S, Akarsu M, Goktay Y, Unsal B, Akpinar H. Evaluation of early atherosclerosis in patients with inflammatory bowel disease. Dig Dis Sci. 2012; 57:2137–2143. PMID: 22466100.
Article
45. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011; 31:986–1000. PMID: 21508345.
46. Gomez I, Foudi N, Longrois D, Norel X. The role of prostaglandin E2 in human vascular inflammation. Prostaglandins Leukot Essent Fatty Acids. 2013; 89:55–63. PMID: 23756023.
Article
47. Mallat Z, Ait-Oufella H, Tedgui A. Regulatory T-cell immunity in atherosclerosis. Trends Cardiovasc Med. 2007; 17:113–118. PMID: 17482092.
Article
48. Taleb S, Tedgui A, Mallat Z. IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles. Arterioscler Thromb Vasc Biol. 2015; 35:258–264. PMID: 25234818.
49. Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu AM, Morton V, Sun MY, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, Simmons A. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity. 2013; 39:521–536. PMID: 24054330.
Article
50. Lusis AJ, Fogelman AM, Fonarow GC. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation. 2004; 110:1868–1873. PMID: 15451808.
51. Marriott I, Rati DM, McCall SH, Tranguch SL. Induction of Nod1 and Nod2 intracellular pattern recognition receptors in murine osteoblasts following bacterial challenge. Infect Immun. 2005; 73:2967–2973. PMID: 15845503.
Article
52. Tada H, Aiba S, Shibata K, Ohteki T, Takada H. Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun. 2005; 73:7967–7976. PMID: 16299289.
Article
53. Ogura Y, Lala S, Xin W, Smith E, Dowds TA, Chen FF, Zimmermann E, Tretiakova M, Cho JH, Hart J, Greenson JK, Keshav S, Nuñez G. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut. 2003; 52:1591–1597. PMID: 14570728.
Article
54. Uehara A, Fujimoto Y, Fukase K, Takada H. Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol. 2007; 44:3100–3111. PMID: 17403538.
Article
55. Uehara A, Imamura T, Potempa J, Travis J, Takada H. Gingipains from Porphyromonas gingivalis synergistically induce the production of proinflammatory cytokines through protease-activated receptors with Toll-like receptor and NOD1/2 ligands in human monocytic cells. Cell Microbiol. 2008; 10:1181–1189. PMID: 18182086.
Article
56. Kanno S, Nishio H, Tanaka T, Motomura Y, Murata K, Ihara K, Onimaru M, Yamasaki S, Kono H, Sueishi K, Hara T. Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice. J Immunol. 2015; 194:773–780. PMID: 25488987.
Article
Full Text Links
  • KJPP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr