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01-03-2013 | CRYSTAL ARTHRITIS (MH PILLINGER, SECTION EDITOR)

Cholesterol Crystals and Inflammation

Authors: Alena Grebe, Eicke Latz

Published in: Current Rheumatology Reports | Issue 3/2013

Abstract

Chronic vascular inflammation is regarded as a crucial aspect of cardiovascular disease. However, the elicitors of this inflammatory response in the vessel wall are currently not well understood. Excessive amounts of cholesterol, an abundant and fundamental lipid molecule in mammalian cells, can initiate the development and progression of atherosclerosis. Accumulation of cholesterol in early atherosclerotic lesions results in the formation of macrophage foam cells, and crystalline cholesterol is found as a characteristic of advanced atherosclerotic plaques. Cholesterol crystals can activate the NLRP3 inflammasome, a multimolecular signaling complex of the innate immune system, resulting in caspase-1 mediated activation and secretion of proinflammatory interleukin-1 family cytokines. Furthermore, crystalline cholesterol is believed to induce plaque rupture by physical disruption of the fibrous cap covering atherosclerotic lesions. Here we review the effect of cholesterol deposition and crystallization on inflammatory responses in cardiovascular diseases.

Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.PubMedCrossRef

Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37.PubMedCrossRef

Stutz A, Golenbock DT, Latz E. Inflammasomes: too big to miss. J Clin Invest. 2009;119(12):3502–11.PubMedCrossRef

Dostert C et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674–7.PubMedCrossRef

Hornung V et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9(8):847–56.PubMedCrossRef

•• Duewell P et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61. Demonstration that cholesterol crystals can activate the NLRP3 inflammasome and contribute to development of atherosclerosis in a murine model.PubMedCrossRef

• Rajamaki K et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5(7):e11765. This paper reports results revealing that human immune cells can be activated by cholesterol crystals to secrete IL-1β cytokines.PubMedCrossRef

Boya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene. 2008;27(50):6434–51.PubMedCrossRef

Chang TY et al. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129–57.PubMedCrossRef

10.

Small DM. George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry. Arteriosclerosis. 1988;8(2):103–29.PubMedCrossRef

11.

Tangirala RK et al. Formation of cholesterol monohydrate crystals in macrophage-derived foam cells. J Lipid Res. 1994;35(1):93–104.PubMed

12.

Kellner-Weibel G et al. Crystallization of free cholesterol in model macrophage foam cells. Arterioscler Thromb Vasc Biol. 1999;19(8):1891–8.PubMedCrossRef

13.

Adams CW, Abdulla YH. The action of human high density lipoprotein on cholesterol crystals. Part 1. Light-microscopic observations. Atherosclerosis. 1978;31(4):465–71.PubMedCrossRef

14.

Abdulla YH, Adams CW. The action of human high density lipoprotein on cholesterol crystals. Part 2. Biochemical observations. Atherosclerosis. 1978;31(4):473–80.PubMedCrossRef

15.

Krut LH. Clearance of subcutaneous implants of cholesterol in the rat promoted by oxidation products of cholesterol. A postulated role for oxysterols in preventing atherosclerosis. Atherosclerosis. 1982;43(1):105–18.PubMedCrossRef

16.

Swartz Jr GM et al. Antibodies to cholesterol. Proc Natl Acad Sci U S A. 1988;85(6):1902–6.PubMedCrossRef

17.

Hammerschmidt DE et al. Cholesterol and atheroma lipids activate complement and stimulate granulocytes. A possible mechanism for amplification of ischemic injury in atherosclerotic states. J Lab Clin Med. 1981;98(1):68–77.PubMed

18.

Sedaghat A, Grundy SM. Cholesterol crystals and the formation of cholesterol gallstones. N Engl J Med. 1980;302(23):1274–7.PubMedCrossRef

19.

Nair PN, Sjogren U, Sundqvist G. Cholesterol crystals as an etiological factor in non-resolving chronic inflammation: an experimental study in guinea pigs. Eur J Oral Sci. 1998;106(2 Pt 1):644–50.PubMedCrossRef

20.

Sjogren U et al. Bone-resorbing activity from cholesterol-exposed macrophages due to enhanced expression of interleukin-1alpha. J Dent Res. 2002;81(1):11–6.PubMedCrossRef

21.

Nissen SE et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med. 2006;354(12):1253–63.PubMedCrossRef

22.

Meuwese MC et al. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA. 2009;301(11):1131–9.PubMedCrossRef

23.

Accad M et al. Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J Clin Invest. 2000;105(6):711–9.PubMedCrossRef

24.

Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.PubMedCrossRef

25.

Wright SD et al. Infectious agents are not necessary for murine atherogenesis. J Exp Med. 2000;191(8):1437–42.PubMedCrossRef

26.

Abela GS, Aziz K. Cholesterol crystals cause mechanical damage to biological membranes: a proposed mechanism of plaque rupture and erosion leading to arterial thrombosis. Clin Cardiol. 2005;28(9):413–20.PubMedCrossRef

27.

Abela GS, Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events—a novel insight into plaque rupture by scanning electron microscopy. Scanning. 2006;28(1):1–10.PubMedCrossRef

28.

Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes. Am J Cardiol. 2009;103(7):959–68.PubMedCrossRef

29.

Galea J et al. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 1996;16(8):1000–6.PubMedCrossRef

30.

Kirii H et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23(4):656–60.PubMedCrossRef

31.

Menu P et al. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis. 2011;2:e137.PubMedCrossRef

32.

Wouters K et al. Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice. Clin Chem Lab Med. 2005;43(5):470–9.PubMedCrossRef

33.

• Razani B et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15(4):534–44. This paper reports results indicating that autophagy regulates NLRP3 inflammasome activation by cholesterol crystals in atherosclerotic plaques.PubMedCrossRef

34.

Abela GS. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation. J Clin Lipidol. 2010;4(3):156–64.PubMedCrossRef

35.

Gordon T et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707–14.PubMedCrossRef

36.

Redondo S et al. Emerging therapeutic strategies to enhance HDL function. Lipids Health Dis. 2011;10:175.PubMedCrossRef

37.

Hewing B, Fisher EA. Rationale for cholesteryl ester transfer protein inhibition. Curr Opin Lipidol. 2012;23(4):372–6.PubMedCrossRef

38.

Schwartz, G.G., et al., Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med, 2012.

39.

Nicklin MJ et al. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med. 2000;191(2):303–12.PubMedCrossRef

40.

Isoda K et al. Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2004;24(6):1068–73.PubMedCrossRef

41.

Devlin CM et al. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A. 2002;99(9):6280–5.PubMedCrossRef

42.

Elhage R et al. Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice. Circulation. 1998;97(3):242–4.PubMedCrossRef

43.

• Ridker PM et al. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597–605. Design of the CANTOS study testing the effect of anti-IL-1β therapy in atherosclerosis. The first human test of the inflammation hypothesis for atherogenesis.PubMedCrossRef

44.

Alexander MR et al. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest. 2012;122(1):70–9.PubMedCrossRef

Title: Cholesterol Crystals and Inflammation
Authors: Alena Grebe
Eicke Latz
Publication date: 01-03-2013
Publisher: Current Science Inc.
Published in: Current Rheumatology Reports / Issue 3/2013
Print ISSN: 1523-3774
Electronic ISSN: 1534-6307
DOI: https://doi.org/10.1007/s11926-012-0313-z

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