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OxLDL-induced IL-1beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation

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Abstract

Objective

IL-1β is a master switch of inflammation and plays an important role in the pathogenesis of vascular disease. During early atherosclerosis development, it is not clearly understood how oxidized low density lipoprotein (oxLDL)induced signaling pathways control NLRP3 inflammasome activation and produce IL-1β and promote foam cells formation.

Methods

The study used THP-1 macrophage as cell model. Western blot quantified the oxLDL-induced NLRP3 inflammasome related proteins. The FACS detected the expression of SR-A and CD36 receptors on the cells, and caspase-1 activation in the cells. The DCFH-DA assayed the reactive oxygen species (ROS). Oil red O staining techniques examined the intracellular lipid droplet.

Results

The OxLDL remarkably increased not only IL-1β mRNA transcription and pro-IL-1β protein synthesis but also IL-1β secretion in human macrophages. The activation of the NLRP3 inflammasome depended on oxLDL-induced generation of ROS, potassium efflux and cathepsin B activity. The OxLDL-induced ROS production that mediates IL-1β maturation mainly depended on the scavenger receptor of CD36 but not SR-A. The secreted IL-1β served as an autocrine function for promoting macrophage foam cells formation.

Conclusions

These findings suggest that oxLDL-induced NLRP3 inflammasome activation mainly depends on CD36 involved in the progression of atherosclerosis by promoting oxLDL-mediated inflammation and foam cell formation.

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References

  1. Hansson GK, Libby P. The immune response in atherosclerosis: a double edged sword. Nat Rev Immunol. 2006;6:508–19.

    Article  CAS  PubMed  Google Scholar 

  2. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;3:587–96.

    Article  Google Scholar 

  3. Mangge H, Hubmann H, Pilz S, Schauenstein K, Renner W, Marz W. Beyond cholesterol-inflammatory cytokines, the key mediators in atherosclerosis. Clin Chem Lab Med. 2004;42:467–74.

    Article  CAS  PubMed  Google Scholar 

  4. Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res. 2008;79:360–76.

    Article  CAS  PubMed  Google Scholar 

  5. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:656–60.

    Article  CAS  PubMed  Google Scholar 

  6. Kamari Y, Werman-Venkert R, Shaish A, Werman A, Harari A, Gonen A, Voronov E, Grosskopf I, Sharabi Y, Grossman E, Iwakura Y, Dinarello CA, Apte RN, Harats D. Differential role and tissue specificity of interleukin-1alpha gene expression in atherogenesis and lipid metabolism. Atherosclerosis. 2007;195:31–8.

    Article  CAS  PubMed  Google Scholar 

  7. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    Article  CAS  PubMed  Google Scholar 

  8. Dinarello CA. Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann NY Acad Sci. 1998;856:1–11.

    Article  CAS  PubMed  Google Scholar 

  9. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.

    Article  CAS  PubMed  Google Scholar 

  10. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10:210–5.

    Article  CAS  PubMed  Google Scholar 

  11. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.

    Article  CAS  PubMed  Google Scholar 

  12. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233–6.

    Article  CAS  PubMed  Google Scholar 

  14. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.

    Article  CAS  PubMed  Google Scholar 

  15. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Khovidhunkit W, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. J Lipid Res. 2003;44:1728–36.

    Article  CAS  PubMed  Google Scholar 

  17. Persson J, Nilsson J, Lindholm MW. Interleukin-1beta and tumour necrosis factor-alpha impede neutral lipid turnover in macrophage-derived foam cells. BMC Immunol. 2008;9:70.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Chen M, Li W, Wang N, Zhu Y, Wang X. ROS and NF-kappaB but not LXR mediate IL-1beta signaling for the downregulation of ATP-binding cassette transporter A1. Am J Physiol Cell Physiol. 2007;292:C1493–501.

    Article  CAS  PubMed  Google Scholar 

  19. Yang H, Chen SC, Tang YQ, Daim YL. Effect of overexpression of human SR-AI on oxLDL uptake and apoptosis in 293T cells. Int Immunopharmacol. 2011;11:1752–7.

    Article  CAS  PubMed  Google Scholar 

  20. Willingham SB, Allen IC, Bergstralh DT, Brickey WJ, Huang MT, Taxman DJ, Duncan JA, Ting JP. NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol. 2009;183:2008–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Fujita Y, Kakino A, Harada-Shiba M, Sato Y, Otsui K, Yoshimoto R, Sawamura T. C-reactive protein uptake by macrophage cell line via class-A scavenger receptor. Clin Chem. 2010;56:478–81.

    Article  CAS  PubMed  Google Scholar 

  22. Mitchell RW, On NH, Del Bigio MR, Miller DW, Hatch GM. Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J Neurochem. 2011;117:735–46.

    Article  CAS  PubMed  Google Scholar 

  23. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang Y, Wang M, Huang K, Zhang Z, Shao N, Zhang Y, Wang W, Wang S. Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun. 2012;425:121–6.

    Article  CAS  PubMed  Google Scholar 

  25. Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem. 2007;282:2871–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14:1583–9.

    Article  PubMed  Google Scholar 

  27. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptor: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–37.

    Article  CAS  PubMed  Google Scholar 

  29. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002;277:49982–8.

    Article  CAS  PubMed  Google Scholar 

  30. Martinon F, Agostini L, Meylan E, Tschopp J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol. 2004;14:1929–34.

    Article  CAS  PubMed  Google Scholar 

  31. Kzhyshkowska J, Neyen C, Gordon S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology. 2012;217:492–502.

    Article  CAS  PubMed  Google Scholar 

  32. Itabe H, Ueda M. Measurement of plasma oxidized low-density lipoprotein and its clinical implications. J Atheroscler Thromb. 2007;14:1–11.

    Article  CAS  PubMed  Google Scholar 

  33. Martin-Fuentes P, Civeira F, Recalde D, Garcia-Otin AL, Jarauta E, Marzo I, Cenarro A. Individual variation of scavenger receptor expression in human macrophages with oxidized low-density lipoprotein is associated with a differential inflammatory response. J Immunol. 2007;179:3242–8.

    CAS  PubMed  Google Scholar 

  34. Kuchibhotla S, Vanegas D, Kennedy DJ, Guy E, Nimako G, Morton RE, Febbraio M. Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II. Cardiovasc Res. 2008;78:185–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest. 2009;119:136–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT. Eklund KK Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE. 2010;5:e11765.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Basic Research program of China (973 Program, Grant No. 2013CB530700).

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Immunology, Tongji University School of Medicine, Medical Research Building, Rm F509, 1239 Siping Road, Shanghai, 200092, China

    Weiwei Liu, Yanlin Yin, Zihui Zhou, Min He & Yalei Dai

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  1. Weiwei Liu
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  2. Yanlin Yin
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  3. Zihui Zhou
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  4. Min He
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Correspondence to Yalei Dai.

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Responsible Editor: Helen Griffiths.

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Liu, W., Yin, Y., Zhou, Z. et al. OxLDL-induced IL-1beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation. Inflamm. Res. 63, 33–43 (2014). https://doi.org/10.1007/s00011-013-0667-3

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  • DOI: https://doi.org/10.1007/s00011-013-0667-3

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