Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice
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 pr...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-11-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821000958 |
| _version_ | 1818401177549668352 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Julia Leipner |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T07:48:19Z |
| format | Article |
| id | doaj.art-2dc928239d7942c88b783de5c24716a3 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T07:48:19Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-2dc928239d7942c88b783de5c24716a32022-12-21T23:10:48ZengElsevierMolecular Metabolism2212-87782021-11-0153101250Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– miceJulia Leipner0Tsai-Sang Dederichs1Alexander von Ehr2Simon Rauterberg3Carolin Ehlert4Julian Merz5Bianca Dufner6Natalie Hoppe7Katja Krebs8Timo Heidt9Constantin von zur Muehlen10Peter Stachon11Klaus Ley12Dennis Wolf13Andreas Zirlik14Christoph Bode15Ingo Hilgendorf16Carmen Härdtner17University Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyLa Jolla Institute for Allergy & Immunology, Division of Inflammation Biology, 9420 Athena Circle, La Jolla, CA, 92037, USAUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyLKH-University Hospital Graz, Department of Cardiology, Auenbruggerplatz 15, 8036, Graz, AustriaUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, GermanyUniversity Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, Germany; Corresponding author. Immunocardiology, Breisacher street 33, 79106, Freiburg i.Br., Germany.University Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, Germany; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2212877821000958AtherosclerosisInterferon regulatory factor 5Macrophage polarization (M1, M2)Plaque stabilizationAnti-inflammationAortic macrophages |
| spellingShingle | 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 Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice Molecular Metabolism Atherosclerosis Interferon regulatory factor 5 Macrophage polarization (M1, M2) Plaque stabilization Anti-inflammation Aortic macrophages |
| title | Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice |
| title_full | Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice |
| title_fullStr | Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice |
| title_full_unstemmed | Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice |
| title_short | Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe–/– mice |
| title_sort | myeloid cell specific irf5 deficiency stabilizes atherosclerotic plaques in apoe mice |
| topic | Atherosclerosis Interferon regulatory factor 5 Macrophage polarization (M1, M2) Plaque stabilization Anti-inflammation Aortic macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821000958 |
| work_keys_str_mv | AT julialeipner myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT tsaisangdederichs myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT alexandervonehr myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT simonrauterberg myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT carolinehlert myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT julianmerz myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT biancadufner myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT nataliehoppe myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT katjakrebs myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT timoheidt myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT constantinvonzurmuehlen myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT peterstachon myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT klausley myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT denniswolf myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT andreaszirlik myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT christophbode myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT ingohilgendorf myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice AT carmenhardtner myeloidcellspecificirf5deficiencystabilizesatheroscleroticplaquesinapoemice |