Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17mediated macrophage accumulation

Sibylle Von Vietinghoff, Ekaterina K. Koltsova, Javier Mestas, Cody J. Diehl, Joseph L. Witztum, Klaus Ley

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Objectives: This study tested whether immunosuppression with mycophenolate mofetil (MMF) inhibits atherosclerosis development in apolipoprotein-Edeficient (Apoe-/-) mice and investigated the mechanism. Background: Chronic vascular inflammation involving both innate and adaptive immunity is central in the development of atherosclerosis, but immunosuppressive treatment is not uniformly beneficial. The immunosuppressive MMF targets lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase. Methods: Young and aged Apoe-/- mice were treated with 30 mg/kg daily MMF during 12 and 3 weeks of a high-fat diet, respectively. Aortic lesion size and composition was investigated by histology and flow cytometry; soluble inflammatory mediators were investigated by enzyme-linked immunosorbent assay. Results: Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in both MMF-treated groups. While systemic immunoglobulin G directed against low-density lipoproteins was not significantly altered, the T-cell cytokine interleukin (IL)-17 was significantly reduced in plasma of MMF-treated mice and supernatants from their aortas after T-cell stimulation. The MMF treatment decreased aortic αβ T-cell receptor+ lymphocyte proliferation and cell numbers. Also, aortic contents of CD11b+CD11c+ cells and their proliferation were reduced in MMF-treated Apoe-/- mice. The IL-17 supplementation restored the number of proliferating aortic CD11b +CD11c+ cells in MMF-treated mice. The IL-17 receptor A was highly expressed on circulating monocytes that are macrophage progenitors. Genetic deletion of IL-17 receptor A or IL-17A reduced inflammatory peritoneal CD11b+CD11c+ macrophage accumulation. Conclusions: The lymphocyte-directed immunosuppressant MMF that curbs IL-17 production was a successful antiatherosclerotic treatment. Our data delineate a role for IL-17 in CD11b+CD11c+ cell accumulation.

Original languageEnglish (US)
Pages (from-to)2194-2204
Number of pages11
JournalJournal of the American College of Cardiology
Issue number21
StatePublished - May 24 2011
Externally publishedYes


  • T cells
  • atherosclerosis
  • immunosuppression
  • interleukin 17
  • macrophage
  • vascular inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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