Letter | Published:

Mast cells promote atherosclerosis by releasing proinflammatory cytokines

Nature Medicine volume 13, pages 719724 (2007) | Download Citation

Abstract

Mast cells contribute importantly to allergic and innate immune responses by releasing various preformed and newly synthesized mediators1,2. Previous studies have shown mast cell accumulation in human atherosclerotic lesions3. This report establishes the direct participation of mast cells in atherogenesis in low-density lipoprotein receptor–deficient (Ldlr−/−) mice4. Atheromata from compound mutant Ldlr−/− KitW-sh/W-sh mice5 showed decreased lesion size, lipid deposition, T-cell and macrophage numbers, cell proliferation and apoptosis, but increased collagen content and fibrous cap development. In vivo, adoptive transfer of syngeneic wild-type or tumor necrosis factor (TNF)-α-deficient mast cells restored atherogenesis to Ldlr−/−KitW-sh/W-sh mice. Notably, neither interleukin (IL)-6- nor interferon (IFN)-γ-deficient mast cells did so, indicating that the inhibition of atherogenesis in Ldlr−/−KitW-sh/W-sh mice resulted from the absence of mast cells and mast cell–derived IL-6 and IFN-γ. Compared with wild-type or TNF-α-deficient mast cells, those lacking IL-6 or IFN-γ did not induce expression of proatherogenic cysteine proteinase cathepsins from vascular cells in vitro or affect cathepsin and matrix metalloproteinase activities in atherosclerotic lesions, implying that mast cell–derived IL-6 and IFN-γ promote atherogenesis by augmenting the expression of matrix-degrading proteases. These observations establish direct participation of mast cells and mast cell–derived IL-6 and IFN-γ in mouse atherogenesis and provide new mechanistic insight into the pathogenesis of this common disease.

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References

  1. 1.

    & The diverse roles of mast cells. J. Exp. Med. 194, F1–F5 (2001).

  2. 2.

    et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749–786 (2005).

  3. 3.

    , & Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries. J. Pathol. 182, 115–122 (1997).

  4. 4.

    , , , & Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J. Clin. Invest. 93, 1885–1893 (1994).

  5. 5.

    et al. Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell-deficient KitW-sh/KitW-sh sash mice. Clin. Exp. Allergy 35, 82–88 (2005).

  6. 6.

    Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

  7. 7.

    Mast cells and susceptibility to experimental atherosclerosis. Science 117, 505–506 (1953).

  8. 8.

    , & Mast cells in rupture-prone areas of human coronary atheromas produce and store TNF-α. Circulation 94, 2787–2792 (1996).

  9. 9.

    Human mast cell cytokines. Clin. Exp. Allergy 26, 13–19 (1996).

  10. 10.

    , , & Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 18, 1707–1715 (1998).

  11. 11.

    , & The chymase, mouse mast cell protease 4, constitutes the major chymotrypsin-like activity in peritoneum and ear tissue. A role for mouse mast cell protease 4 in thrombin regulation and fibronectin turnover. J. Exp. Med. 198, 423–431 (2003).

  12. 12.

    et al. The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice. Proc. Natl. Acad. Sci. USA 92, 3754–3758 (1995).

  13. 13.

    et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

  14. 14.

    et al. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167, 835–848 (2005).

  15. 15.

    & Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 192, 455–462 (2000).

  16. 16.

    et al. Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. J. Exp. Med. 175, 1003–1012 (1992).

  17. 17.

    et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22, 93–104 (2005).

  18. 18.

    et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109, 1408–1414 (2004).

  19. 19.

    et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 111, 897–906 (2003).

  20. 20.

    et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113, 98–107 (2006).

  21. 21.

    et al. Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115, 2065–2075 (2007).

  22. 22.

    et al. A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J. Biol. Chem. 280, 9291–9296 (2005).

  23. 23.

    , , , & Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J. Biol. Chem. 267, 7258–7262 (1992).

  24. 24.

    et al. Molecular mechanisms regulating induction of interleukin-6 gene transcription by interferon-gamma. Eur. J. Immunol. 27, 3022–3030 (1997).

  25. 25.

    , & Interferon-gamma regulation of interleukin 6 in monocytic cells. Am. J. Physiol. 267, L564–L568 (1994).

  26. 26.

    et al. c-kit gene was not transcribed in cultured mast cells of mast cell-deficient Wsh/Wsh mice that have a normal number of erythrocytes and a normal c-kit coding region. Blood 80, 1448–1453 (1992).

  27. 27.

    , , , & Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394, 200–203 (1998).

  28. 28.

    et al. Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ. Res. 92, 493–500 (2003).

  29. 29.

    , , & Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase. J. Clin. Invest. 97, 1589–1596 (1996).

  30. 30.

    , & Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 9, 974–980 (1995).

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Acknowledgements

The authors thank E. Shvartz and Y. Yuan for technical assistance, K. Williams for editorial assistance and G. Caughey for comments on the manuscript. This work is supported by US National Institutes of Health grants HL60942 and HL67283 (G.-P.S.), HL56985 (P.L.), HL67249 (G.K.S.) and HL75026 (P.J.W.).

Author information

Author notes

    • Jiusong Sun
    • , Galina K Sukhova
    • , Paul J Wolters
    •  & Min Yang

    These authors contributed equally to this study.

Affiliations

  1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cardiovascular Medicine NRB-7, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    • Jiusong Sun
    • , Galina K Sukhova
    • , Min Yang
    • , Shiro Kitamoto
    • , Peter Libby
    • , Lindsey A MacFarlane
    •  & Guo-Ping Shi
  2. Department of Medicine, University of California, HSE-201, 513 Parnassus Avenue, San Francisco, California 94143, USA.

    • Paul J Wolters
    •  & Jon Mallen-St Clair
  3. Department of Rheumatology, Nanfang Hospital and Nanfang Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.

    • Min Yang

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Contributions

J.S. generated compound mutant mice, produced atherosclerosis, harvested tissues, performed mast cell reconstitution experiments and analyzed lesions. G.K.S. performed all the immunohistochemistry experiments and participated in data analysis. P.J.W. helped with the design of experiments using the mast cell–null mice and mast cell reconstitution, data analysis and manuscript editing. M.Y. helped with lesion content characterization. S.K. helped with initial mouse breeding and genotyping. P.L. helped in experiment design and manuscript editing. L.A.M. performed immunostaining and lesion cell content measurement. J.M.-S.C. helped with BMMC culture. G.-P.S. designed the experiment, performed the cysteine protease activity assay, participated in data analysis and prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guo-Ping Shi.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Confirmation of c-Kit monoclonal antibody specificity.

  2. 2.

    Supplementary Fig. 2

    IFN-γ expression in mouse aortic atherosclerotic lesions.

  3. 3.

    Supplementary Fig. 3

    BMMC morphology.

  4. 4.

    Supplementary Fig. 4

    BMMC fluorescence-activated cell sorting analysis.

  5. 5.

    Supplementary Fig. 5

    [125I]JPM labeling of mouse endothelial cell cysteine protease cathespins.

  6. 6.

    Supplementary Table 1

    Protease activity in BMMC lysates.

  7. 7.

    Supplementary Table 2

    Mouse plasma lipid and serum amyloid A contents.

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DOI

https://doi.org/10.1038/nm1601

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