Letter | Published:

Mast cells promote atherosclerosis by releasing proinflammatory cytokines

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


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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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.


  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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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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