Mast cells promote atherosclerosis by releasing proinflammatory cytokines
Top Cited Papers
- 3 June 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 13 (6), 719-724
- https://doi.org/10.1038/nm1601
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.This publication has 28 references indexed in Scilit:
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