Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe-/- mice.
Mol Metab
; 53: 101250, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-33991749
ABSTRACT
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 Tgfß 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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Apolipoproteínas E
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Células Mieloides
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Fatores Reguladores de Interferon
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Placa Aterosclerótica
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article