Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice

Julia Leipner, Tsai Sang Dederichs, Alexander von Ehr, Simon Rauterberg, Carolin Ehlert, Julian Merz, Bianca Dufner, Natalie Hoppe, Katja Krebs, Timo Heidt, Constantin von zur Muehlen, Peter Stachon, Klaus Ley, Dennis Wolf, Andreas Zirlik, Christoph Bode, Ingo Hilgendorf, Carmen Härdtner

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Objective: Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis. Methods: Female Apoe–/– LysmCre/+ Irf5fl/fl and Apoe −/− Irf5fl/fl mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques. Results: Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo. While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5-deficient Apoe–/– mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfβ expression. Irf5-deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5-deficient macrophages proliferated less in the plaque. Conclusion: Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.

Original languageEnglish (US)
Article number101250
JournalMolecular Metabolism
StatePublished - Nov 2021
Externally publishedYes


  • Anti-inflammation
  • Aortic macrophages
  • Atherosclerosis
  • Interferon regulatory factor 5
  • Macrophage polarization (M1, M2)
  • Plaque stabilization

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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