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A Spotlight on the Underlying Activation Mechanisms of the NLRP3 Inflammasome and its Role in Atherosclerosis: A Review

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Abstract

The world’s number one cause of death is cardiovascular diseases. The pathogenesis of different disease entities in the cardiovascular disease spectrum is complicated and multifactorial. Inflammation in these complicated etiologies serves as a key position and is a significant cause of atherosclerosis, which contributes to the underlying pathology. Therefore, therapeutic targeting of inflammatory pathways in patients with cardiovascular diseases such as atherosclerosis enhances cardiovascular results. Inflammasomes are intracellular protein complexes engaged in atherosclerosis pathogenesis and activated by multiple danger signals. Emerging proof has revealed that Nod-like receptor protein 3 (NLRP3) inflammasome, which regulates caspase-1 activation and later pro-interleukin processing, triggers inflammatory reactions in the vascular wall and leads to atherosclerotic plaque formation. Inflammasome-mediated signaling interference could decrease inflammation and mitigate illness severity. In this section, we provide an overview of the present literature on the underlying mechanisms leading to the activation of NLRP3 inflammasome and the role of NLRP3 inflammasome in the progression of atherogenesis and highlight the possibility of therapeutic interventions due to mechanisms involved in the of inhibition of NLRP3 activation.

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References

  1. Medzhitov, R. 2008. Origin and physiological roles of inflammation. Nature. 454: 428–435.

    Article  PubMed  CAS  Google Scholar 

  2. Lamkanfi, M., and V.M. Dixit. 2014. Mechanisms and functions of inflammasomes. Cell. 157: 1013–1022.

    Article  PubMed  CAS  Google Scholar 

  3. Amin, J., D. Boche, and S. Rakic. 2017. What do we know about the inflammasome in humans? Brain Pathol 27: 192–204.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schroder, K., R. Zhou, and J. Tschopp. 2010. The NLRP3 inflammasome: A sensor for metabolic danger? Science. 327: 296–300.

    Article  PubMed  CAS  Google Scholar 

  5. Libby. Interleukin-1 beta as a target for atherosclerosis therapy: Jour of the Amer Colle of Cardio. 2017: 18; 2278–2289.

  6. Broz, P., and V.M. Dixit. 2016. Inflammasomes: Mechanism of assembly, regulation and signaling. Nat Rev Immunol 16: 407–420.

    Article  PubMed  CAS  Google Scholar 

  7. Vanaja, S.K., V.A. Rathinam, and K.A. Fitzgerald. 2015. Mechanisms of inflammasome activation: Recent advances and novel insights. Trends Cell Biol 25: 308–315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bauernfeind, F.G., et al. 2009. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183: 787–791.

    Article  PubMed  CAS  Google Scholar 

  9. Lemmers, B., L. Salmena, N. Bidère, H. Su, E. Matysiak-Zablocki, K. Murakami, P.S. Ohashi, A. Jurisicova, M. Lenardo, R. Hakem, and A. Hakem. 2007. Essential role for caspase-8 in toll-like receptors and NFκB signaling. J Biol Chem 282: 7416–7423.

    Article  PubMed  CAS  Google Scholar 

  10. Gurung, P., P.K. Anand, R.K.S. Malireddi, L. Vande Walle, N. van Opdenbosch, C.P. Dillon, R. Weinlich, D.R. Green, M. Lamkanfi, and T.D. Kanneganti. 2014. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol 192: 1835–1846.

    Article  PubMed  CAS  Google Scholar 

  11. Py, B.F., et al. 2013. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasomes activity. Mol Cell 49: 331–338.

    Article  PubMed  CAS  Google Scholar 

  12. Bauernfeind, F., A. Rieger, F.A. Schildberg, P.A. Knolle, J.L. Schmid-Burgk, and V. Hornung. 2012. NLRP3 inflammasome activity is negatively controlled by miR-223. J Immunol 189: 4175–4181.

    Article  PubMed  CAS  Google Scholar 

  13. Haneklaus, M., J.D. O’Neil, A.R. Clark, S.L. Masters, and L.A.J. O’Neill. 2017. The RNA-binding protein tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome. J Biol Chem 292: 6869–6881.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Stutz, A., C.C. Kolbe, R. Stahl, G.L. Horvath, B.S. Franklin, O. van Ray, R. Brinkschulte, M. Geyer, F. Meissner, and E. Latz. 2017. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med 214: 1725–1736.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hernandez-Cuellar, E., K. Tsuchiya, H. Hara, R. Fang, S. Sakai, I. Kawamura, S. Akira, and M. Mitsuyama. 2012. Nitric oxide inhibits the NLRP3 inflammasome. J Immunol 189: 5113–5117.

    Article  PubMed  CAS  Google Scholar 

  16. Muñoz-Planillo, R., P. Kuffa, G. Martínez-Colón, B.L. Smith, T.M. Rajendiran, and G. Núñez. 2013. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 38: 1142–1153.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. He, Y., M. Zeng, D. Yang, B. Motro, and G. Núñez. 2016. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 530: 354–357.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Karmakar, M., M.A. Katsnelson, G.R. Dubyak, and E. Pearlman. 2016. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat Commun 7: 10555.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Katsnelson, M.A., L.G. Rucker, H.M. Russo, and G.R. Dubyak. 2015. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J Immunol 194: 3937–3952.

    Article  PubMed  CAS  Google Scholar 

  20. Murakami, T., J. Ockinger, J. Yu, V. Byles, A. McColl, A.M. Hofer, and T. Horng. 2012. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci 109: 11282–11287.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Csordás, G., and G. Hajnóczky. 1787. SR/ER–mitochondrial local communication: Calcium and ROS. Biochim Biophys Acta Bioenerg 2009: 1352–1362.

    Google Scholar 

  22. Schorn, C., B. Frey, K. Lauber, C. Janko, M. Strysio, H. Keppeler, U.S. Gaipl, R.E. Voll, E. Springer, L.E. Munoz, G. Schett, and M. Herrmann. 2011. Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem 286: 35–41.

    Article  PubMed  CAS  Google Scholar 

  23. Verhoef, P.A., S.B. Kertesy, K. Lundberg, J.M. Kahlenberg, and G.R. Dubyak. 2005. Inhibitory effects of chloride on the activation of caspase-1, IL-1β secretion, and cytolysis by the P2X7 receptor. J Immunol 175: 7623–7634.

    Article  PubMed  CAS  Google Scholar 

  24. Compan, V., A. Baroja-Mazo, G. López-Castejón, A.I. Gomez, C.M. Martínez, D. Angosto, M.T. Montero, A.S. Herranz, E. Bazán, D. Reimers, V. Mulero, and P. Pelegrín. 2012. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 37: 487–500.

    Article  PubMed  CAS  Google Scholar 

  25. Tang, T., X. Lang, C. Xu, X. Wang, T. Gong, Y. Yang, J. Cui, L. Bai, J. Wang, W. Jiang, and R. Zhou. 2017. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat Commun 8: 202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Shimada, K., T.R. Crother, J. Karlin, J. Dagvadorj, N. Chiba, S. Chen, V.K. Ramanujan, A.J. Wolf, L. Vergnes, D.M. Ojcius, A. Rentsendorj, M. Vargas, C. Guerrero, Y. Wang, K.A. Fitzgerald, D.M. Underhill, T. Town, and M. Arditi. 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36: 401–414.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Shi, H., Y. Wang, X. Li, X. Zhan, M. Tang, M. Fina, L. Su, D. Pratt, C.H. Bu, S. Hildebrand, S. Lyon, L. Scott, J. Quan, Q. Sun, J. Russell, S. Arnett, P. Jurek, D. Chen, V.V. Kravchenko, J.C. Mathison, E.M.Y. Moresco, N.L. Monson, R.J. Ulevitch, and B. Beutler. 2016. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol 17: 250–258.

    Article  PubMed  CAS  Google Scholar 

  28. Groß, C.J., R. Mishra, K.S. Schneider, G. Médard, J. Wettmarshausen, D.C. Dittlein, H. Shi, O. Gorka, P.A. Koenig, S. Fromm, G. Magnani, T. Ćiković, L. Hartjes, J. Smollich, A.A.B. Robertson, M.A. Cooper, M. Schmidt-Supprian, M. Schuster, K. Schroder, P. Broz, C. Traidl-Hoffmann, B. Beutler, B. Kuster, J. Ruland, S. Schneider, F. Perocchi, and O. Groß. 2016. K+efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity. 45: 761–773.

    Article  PubMed  CAS  Google Scholar 

  29. Halle, A., V. Hornung, G.C. Petzold, C.R. Stewart, B.G. Monks, T. Reinheckel, K.A. Fitzgerald, E. Latz, K.J. Moore, and D.T. Golenbock. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9: 857–865.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hornung, V., F. Bauernfeind, A. Halle, E.O. Samstad, H. Kono, K.L. Rock, K.A. Fitzgerald, and E. Latz. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9: 847–856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wang, Z., W. Hu, C. Lu, Z. Ma, S. Jiang, C. Gu, D. Acuña-Castroviejo, and Y. Yang. 2018. Targeting NLRP3 (nucleotide-binding domain, Leucine-rich–containing family, pyrin domain–Containing-3) inflammasome in cardiovascular disorders. Arterioscler Thromb Vasc Biol 38: 2765–2779.

    Article  PubMed  CAS  Google Scholar 

  32. Karasawa, T., and M. Takahashi. 2017. Role of NLRP3 inflammasomes in atherosclerosis. Review. J Atheroscler Thromb 24: 000–000.

    Article  CAS  Google Scholar 

  33. Zheng, F., S. Xing, Z. Gong, and Q. Xing. 2013. NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. Heart Lung Circ 22: 746–750.

    Article  PubMed  Google Scholar 

  34. Varghese, G.P., L. Folkersen, R.J. Strawbridge, et al. 2016. NLRP3 inflammasome expression and activation in human atherosclerosis. J Am Heart Assoc 5: 3031.

    Google Scholar 

  35. Shi, X., W.L. Xie, W.W. Kong, D. Chen, and P. Qu. 2015. Expression of the NLRP3 inflammasome in carotid atherosclerosis. J Stroke Cerebrovasc Dis 24: 2455–2466.

    Article  PubMed  Google Scholar 

  36. Duewell, P., H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, G.S. Abela, L. Franchi, G. Nuñez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, and E. Latz. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 464: 1357–1361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hendrikx, T., M.L.J. Jeurissen, P.J. Van Gorp, et al. 2015. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr−/− mice. FEBS J 282: 2327–2338.

    Article  PubMed  CAS  Google Scholar 

  38. Wang, R., Y. Wang, and N. Muetal. 2017. Activation of NLRP3inflammasomes contributes to hyperhomocysteinemia-aggravated inflammation and atherosclerosis in apoE-deficient mice. Lab Investig 97: 922–934.

    Article  PubMed  CAS  Google Scholar 

  39. Ding, Z., S. Liu, X. Wang, Y. Dai, M. Khaidakov, X. Deng, Y. Fan, D. Xiang, and J.L. Mehta. 2014. LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: Implications in atherogenesis. Cardiovasc Res 103: 619–628.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Mehta, J.L., N. Sanada, C.P. Hu, et al. 2007. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. J Circ Res 100: 1634–1642.

    Article  CAS  Google Scholar 

  41. Chen, L., Q. Yao, S. Xu, H. Wang, and P. Qu. 2018. Inhibition of the NLRP3 inflammasome attenuates foam cell formation of THP-1 macrophages by suppressing ox-LDL uptake and promoting cholesterol efflux. Biochem Biophys Res Commun 495: 382–387.

    Article  PubMed  CAS  Google Scholar 

  42. Tumurkhuu, G., K. Shimada, J. Dagvadorj, et al. 2016. Ogg1-dependent DNA repair regulates NLRP3 inflammasome and prevents atherosclerosis. Circ Res 119: 76–90.

    Article  CAS  Google Scholar 

  43. Wang, Y., Z. Han, Y. Fan, J. Zhang, K. Chen, L. Gao, H. Zeng, J. Cao, and C. Wang. 2017. MicroRNA-9 inhibits NLRP3 inflammasome activation in human atherosclerosis inflammation cell models through the JAK1/STAT signaling pathway. Cell Physiol Biochem 41: 1555–1571.

    Article  PubMed  CAS  Google Scholar 

  44. Rajamaki, K., J. Lappalainen, K. Oorni, et al. 2010. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 7: e11765.

    Article  CAS  Google Scholar 

  45. Tabas, I., and A.H. Lichtman. 2017. Monocyte-macrophages and T cells in atherosclerosis. Immun. 4: 621–634.

    Article  CAS  Google Scholar 

  46. Hendrikx T, Jeurissen M.L.J, van Gorp P. J, et al. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development inLdlr−/− mice. FEBS J. 2015;12:2327–2338.

  47. Yin, Y., X. Li, X. Sha, et al. 2015. Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. Arterio, Thromb, and Vascu Bio 35: 804–816.

    Article  CAS  Google Scholar 

  48. Wu, X., H. Zhang, W. Qi, et al. 2018. Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death & Disease 2: 171.

    Article  CAS  Google Scholar 

  49. Mestas, J., and K. Ley. 2008. Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 6: 228–232.

    Article  CAS  Google Scholar 

  50. Sheikine, Y., and A. Sirsjö. 2008. CXCL16/SR-PSOX-A friend or a foe in atherosclerosis? Atherosc 197: 487–495.

    Article  CAS  Google Scholar 

  51. Kawaguchi, M., M. Takahashi, T. Hata, Y. Kashima, F. Usui, H. Morimoto, A. Izawa, Y. Takahashi, J. Masumoto, J. Koyama, M. Hongo, T. Noda, J. Nakayama, J. Sagara, S.’. Taniguchi, and U. Ikeda. 2011. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Cir. 123: 594–604.

    CAS  Google Scholar 

  52. Fang, L., K.K. Wang, P.F. Zhang, T. Li, Z.L. Xiao, M. Yang, and Z.X. Yu. 2020. Nucleolin promotes Ang II-induced phenotypic transformation of vascular smooth muscle cells by regulating EGF and PDGF-BB. J Cell Mol Med 24: 1917–1933.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Bennett, M.R., S. Sinha, and G.K. Owens. 2016. Vascular smooth muscle cells in atherosclerosis. Circ Res 118: 692–702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Wen, C., X. Yang, Z. Yan, et al. 2013. Nlrp3 inflammasome is activated and required for vascular smooth muscle cell calcification. Int J Cardiol 168: 2242–2247.

    Article  PubMed  Google Scholar 

  55. Man, S.M., Q. Zhu, L. Zhu, Z. Liu, R. Karki, A. Malik, D. Sharma, L. Li, R.K.S. Malireddi, P. Gurung, G. Neale, S.R. Olsen, R.A. Carter, D.J. McGoldrick, G. Wu, D. Finkelstein, P. Vogel, R.J. Gilbertson, and T.D. Kanneganti. 2015. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell. 162: 45–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Luchetti, F., R. Crinelli, E. Cesarini, B. Canonico, L. Guidi, C. Zerbinati, G. di Sario, L. Zamai, M. Magnani, S. Papa, and L. Iuliano. 2017. Endothelial cells, endoplasmic reticulum stress and oxysterols. Redox Biol 13: 581–587.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Çimen, I., B. Kocatürk, S. Koyuncu, et al. 2016. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci Transl Med 8: 126.

    Article  CAS  Google Scholar 

  58. Rsazani, B., C. Feng, T. Coleman, et al. 2012. Autophagy links inflammasomes to athero- sclerotic progression. Cell Metab 15: 534–544.

    Article  CAS  Google Scholar 

  59. Pols, T.W., M. Nomura, T. Harach, et al. 2011. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14: 747–757.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan

    Anam Liaqat, Fatima Shoukat & Arif-Ullah Khan

  2. Armed Forces Institute of Cardiology, National Institute of Heart Diseases, Rawalpindi, Pakistan

    Muhammad Asad

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  1. Anam Liaqat
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Highlights

• Cardiovascular diseases involving heart and vasculature disorders are a serious global health burden that is presently the world’s leading cause of death.

• Multiple danger signals such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein triggered NLRP3 inflammasome activation in macrophages to initiate inflammatory reactions in atherosclerotic lesions.

• Understanding NLRP3 inflammasome activation mechanisms will allow its particular inhibitors to be developed to treat NLRP3-related illnesses

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Liaqat, A., Asad, M., Shoukat, F. et al. A Spotlight on the Underlying Activation Mechanisms of the NLRP3 Inflammasome and its Role in Atherosclerosis: A Review. Inflammation 43, 2011–2020 (2020). https://doi.org/10.1007/s10753-020-01290-1

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