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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178123/ https://www.ncbi.nlm.nih.gov/pubmed/33991749 http://dx.doi.org/10.1016/j.molmet.2021.101250 |
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author | Leipner, Julia Dederichs, Tsai-Sang von Ehr, Alexander Rauterberg, Simon Ehlert, Carolin Merz, Julian Dufner, Bianca Hoppe, Natalie Krebs, Katja Heidt, Timo von zur Muehlen, Constantin Stachon, Peter Ley, Klaus Wolf, Dennis Zirlik, Andreas Bode, Christoph Hilgendorf, Ingo Härdtner, Carmen |
author_facet | Leipner, Julia Dederichs, Tsai-Sang von Ehr, Alexander Rauterberg, Simon Ehlert, Carolin Merz, Julian Dufner, Bianca Hoppe, Natalie Krebs, Katja Heidt, Timo von zur Muehlen, Constantin Stachon, Peter Ley, Klaus Wolf, Dennis Zirlik, Andreas Bode, Christoph Hilgendorf, Ingo Härdtner, Carmen |
author_sort | Leipner, Julia |
collection | PubMed |
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(–/–)Lysm(Cre/+)Irf5(fl/fl) and Apoe(−/−)Irf5(fl/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. |
format | Online Article Text |
id | pubmed-8178123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-81781232021-06-15 Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe(–/–) mice Leipner, Julia Dederichs, Tsai-Sang von Ehr, Alexander Rauterberg, Simon Ehlert, Carolin Merz, Julian Dufner, Bianca Hoppe, Natalie Krebs, Katja Heidt, Timo von zur Muehlen, Constantin Stachon, Peter Ley, Klaus Wolf, Dennis Zirlik, Andreas Bode, Christoph Hilgendorf, Ingo Härdtner, Carmen Mol Metab Original Article 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(–/–)Lysm(Cre/+)Irf5(fl/fl) and Apoe(−/−)Irf5(fl/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. Elsevier 2021-05-12 /pmc/articles/PMC8178123/ /pubmed/33991749 http://dx.doi.org/10.1016/j.molmet.2021.101250 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Leipner, Julia Dederichs, Tsai-Sang von Ehr, Alexander Rauterberg, Simon Ehlert, Carolin Merz, Julian Dufner, Bianca Hoppe, Natalie Krebs, Katja Heidt, Timo von zur Muehlen, Constantin Stachon, Peter Ley, Klaus Wolf, Dennis Zirlik, Andreas Bode, Christoph Hilgendorf, Ingo Härdtner, Carmen Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe(–/–) mice |
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 | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178123/ https://www.ncbi.nlm.nih.gov/pubmed/33991749 http://dx.doi.org/10.1016/j.molmet.2021.101250 |
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