Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways

Nature Medicine volume 10, pages 416–421 (2004)Cite this article

Abstract

Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall1. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial2,3,4. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Deficiency of MyD88, but not of the bacterial LPS receptor CD14, markedly reduces atherosclerosis in Apoe−/− mice.
Figure 2: RNA expression profiling of mouse aortas reveals reduced chemokine expression in the absence of MyD88.
Figure 3: MCP-1 protein levels and macrophage recruitment are decreased in the absence of MyD88.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).

    Article  CAS  Google Scholar 

  2. Ismail, A., Khosravi, H. & Olson, H. The role of infection in atherosclerosis and coronary artery disease: a new therapeutic target. Heart Dis. 1, 233–240 (1999).

    CAS  Google Scholar 

  3. Epstein, S.E. et al. Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry. Arterioscler. Thromb. Vasc. Biol. 20, 1417–1420 (2000).

    Article  CAS  Google Scholar 

  4. Frishman, W.H. & Ismail, A.A. Role of infection in atherosclerosis and coronary artery disease: a new therapeutic target? Cardiol. Rev. 10, 199–210 (2002).

    Article  Google Scholar 

  5. Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  Google Scholar 

  6. Binder, C.J. et al. Innate and acquired immunity in atherogenesis. Nat. Med. 8, 1218–26 (2002).

    Article  CAS  Google Scholar 

  7. Chow, J.C., Young, D.W., Golenbock, D.T., Christ, W.J. & Gusovsky, F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 274, 10689–10692 (1999).

    Article  CAS  Google Scholar 

  8. Xu, X.H. et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 104, 3103–3108 (2001).

    Article  CAS  Google Scholar 

  9. Vink, A. et al. In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation 106, 1985–1990 (2002).

    Article  CAS  Google Scholar 

  10. Kiechl, S. et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 347, 185–192 (2002).

    Article  CAS  Google Scholar 

  11. Edfeldt, K., Swedenborg, J., Hansson, G.K. & Yan, Z.Q. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105, 1158–1161 (2002).

    Article  CAS  Google Scholar 

  12. Wright, S.D. et al. Infectious agents are not necessary for murine atherogenesis. J. Exp. Med. 191, 1437–1442 (2000).

    Article  CAS  Google Scholar 

  13. Tanaka, E. et al. Disparity of MCP-1 mRNA and protein expressions between the carotid artery and the aorta in WHHL rabbits: one aspect involved in the regional difference in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23, 244–250 (2003).

    Article  CAS  Google Scholar 

  14. Mach, F. The role of chemokines in atherosclerosis. Curr. Atheroscler. Rep. 3, 243–251 (2001).

    Article  CAS  Google Scholar 

  15. Burke-Gaffney, A., Brooks, A.V. & Bogle, R.G. Regulation of chemokine expression in atherosclerosis. Vascul. Pharmacol. 38, 283–292 (2002).

    Article  CAS  Google Scholar 

  16. Gosling, J. et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J. Clin. Invest. 103, 773–778 (1999).

    Article  CAS  Google Scholar 

  17. Boring, L., Gosling, J., Cleary, M. & Charo, I.F. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394, 894–897 (1998).

    Article  CAS  Google Scholar 

  18. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998).

    Article  CAS  Google Scholar 

  19. Kirii, H. et al. Lack of interleukin-1β decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 656–660 (2003).

    Article  CAS  Google Scholar 

  20. Elhage, R. et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res. 59, 234–240 (2003).

    Article  CAS  Google Scholar 

  21. Bulut, Y. et al. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J. Immunol. 168, 1435–1440 (2002).

    Article  CAS  Google Scholar 

  22. Walton, K.A. et al. Receptors involved in the oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine-mediated synthesis of interleukin-8. A role for Toll-like receptor 4 and a glycosylphosphatidylinositol-anchored protein. J. Biol. Chem. 278, 29661–29666 (2003).

    Article  CAS  Google Scholar 

  23. Raschi, E. et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 101, 3495–3500 (2003).

    Article  CAS  Google Scholar 

  24. Kanters, E. et al. Inhibition of NF-κB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 112, 1176–1185 (2003).

    Article  CAS  Google Scholar 

  25. Pahl, H.L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866 (1999).

    Article  CAS  Google Scholar 

  26. Lawrence, T., Gilroy, D.W., Colville-Nash, P.R. & Willoughby, D.A. Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7, 1291–1297 (2001).

    Article  CAS  Google Scholar 

  27. Moore, K.J. et al. Divergent response to LPS and bacteria in CD14-deficient murine macrophages. J. Immunol. 165, 4272–4280 (2000).

    Article  CAS  Google Scholar 

  28. Kunjathoor, V.V., Wilson, D.L. & LeBoeuf, R.C. Increased atherosclerosis in streptozotocin-induced diabetic mice. J. Clin. Invest. 97, 1767–1773 (1996).

    Article  CAS  Google Scholar 

  29. Kunjathoor, V.V., Chiu, D.S., O'Brien, K.D. & LeBoeuf, R.C. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 22, 462–468 (2002).

    Article  CAS  Google Scholar 

  30. Tangirala, R.K., Rubin, E.M. & Palinski, W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J. Lipid Res. 36, 2320–2328 (1995).

    CAS  Google Scholar 

  31. Saal, L.H. et al. BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data. Genome Biol. 3, SOFTWARE0003 (2002).

  32. Moore, K.J., Naito, T., Martin, C. & Kelley, V.R. Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy. J. Immunol. 157, 433–440 (1996).

    CAS  Google Scholar 

  33. Kunjathoor, V.V. et al. 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. 277, 49982–49988 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants HL66678, HL45098, RR14466 and DK50305. H.B. is supported by the Swedish Research Council. We thank X. Li for assistance with the statistical analysis and C. Chase for technical assistance with the mouse atherosclerosis studies.

Author information

Author notes

  1. Harry Björkbacka and Vidya V Kunjathoor: These authors contributed equally to this work.

Authors and Affiliations

  1. Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Harry Björkbacka, Vidya V Kunjathoor, Kathryn J Moore, Stephanie Koehn, Christine M Ordija, Melinda A Lee & Mason W Freeman

  2. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Terry Means & Andrew D Luster

  3. Division of Infectious Diseases & Immunology, University of Massachusetts Medical School, Worcester, 01655, MA, USA

    Kristen Halmen & Douglas T Golenbock

Authors
  1. Harry Björkbacka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vidya V Kunjathoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathryn J Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie Koehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine M Ordija
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Melinda A Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Terry Means
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kristen Halmen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew D Luster
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Douglas T Golenbock
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mason W Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mason W Freeman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Björkbacka, H., Kunjathoor, V., Moore, K. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10, 416–421 (2004). https://doi.org/10.1038/nm1008

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1008

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing