| 51. |
- Edsfeldt, Andreas, et al.
(författare)
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Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 43:19, s. 1864-1877
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Inflammation is a key factor in atherosclerosis. The transcription factor interferon regulatory factor-5 (IRF5) drives macrophages towards a pro-inflammatory state. We investigated the role of IRF5 in human atherosclerosis and plaque stability.METHODS AND RESULTS: Bulk RNA sequencing from the Carotid Plaque Imaging Project biobank were used to mine associations between major macrophage associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were used for validation. The effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE-/- mice was studied in an inducible model of plaque rupture. Interferon regulatory factor-5 and ITGAX/CD11c were identified as the macrophage associated genes with the strongest associations with symptomatic carotid disease. Expression of IRF5 and ITGAX/CD11c correlated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and with each other. Macrophages were the predominant CD11c-expressing immune cells in the plaque by CyTOF and immunohistochemistry. Interferon regulatory factor-5 immunopositive areas were predominantly found within CD11c+ areas with a predilection for the shoulder region, the area of the human plaque most prone to rupture. Accordingly, an inducible plaque rupture model of ApoE-/-Irf5-/- mice had significantly lower frequencies of carotid plaque ruptures, smaller necrotic cores, and less CD11c+ macrophages than their IRF5-competent counterparts.CONCLUSION: Using complementary evidence from data from human carotid endarterectomies and a murine model of inducible rupture of carotid artery plaque in IRF5-deficient mice, we demonstrate a mechanistic link between the pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and its vulnerability to rupture.KEY QUESTION: The transcription factor interferon regulatory factor-5 (IRF5) is a master regulator of macrophage activation that has been shown to have a role in murine atherogenesis. Its role in human atherosclerosis and its complications is unknown.KEY FINDING: Interferon regulatory factor-5 is linked to plaque vulnerability and symptoms in human carotid endarterectomies. In a murine model of inducible carotid artery plaque rupture, IRF5 drives plaque rupture. Interferon regulatory factor-5 modulates macrophage phenotype and it colocalises with CD11c+ macrophages at the plaque shoulder.TAKE-HOME MESSAGE: We demonstrate a mechanistic link between the IRF5, plaque macrophages, and plaque vulnerability to rupture. Interferon regulatory factor-5 is a potential candidate therapeutic target in human atherosclerosis.
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| 52. |
- Seneviratne, Anusha N., et al.
(författare)
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Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis
- 2017
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Ingår i: Circulation. - 0009-7322. ; 136:5, s. 1140-1154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND—: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis), promotes lesion growth and establishment of a necrotic core. The transcription factor Interferon Regulatory Factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS—: We investigated the role of IRF5 in atherosclerosis in two complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared then lesion development was assessed in a model of shear stress modulated vulnerable plaque formation. RESULTS—: Both lesion size and necrotic core size were significantly reduced in ApoEIrf5 mice compared to IRF5 competent ApoE mice. Necrotic core size was also reduced in the model of shear stress modulated vulnerable plaque formation. A significant loss of CD11c macrophages was evident in ApoEIrf5 mice in the aorta, draining lymph nodes and in bone marrow cell cultures, indicating that IRF5 maintains CD11c macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c macrophages displayed a significant increase in expression of the efferocytosis regulating integrin-β3 and its ligand milk fat globule-EGF factor 8 protein (Mfge8) and enhanced efferocytosis in vitro and in situ. CONCLUSIONS—: IRF5 is detrimental in atherosclerosis by promoting the maintenance of pro-inflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
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| 53. |
- Strom, Asa C., et al.
(författare)
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B regulatory cells are increased in hypercholesterolaemic mice and protect from lesion development via IL-10
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 114:4, s. 835-847
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Tidskriftsartikel (refereegranskat)abstract
- Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (B-reg) have been described. In experimental arthritis and lupus-like disease, B-reg are contained within the CD21(hi)CD23(hi)CD24(hi) B cell pool The existence and role of B-reg in vascular disease is not known. We sought to investigate the existence, identity and location of B-reg in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E-/- (ApoE(-/-)) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE(-/-) mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21(hi)CD23(hi)CD24(hi) B cells are unexpectedly increased in the draining LNs of ApoE(-/-) mice. Adoptive transfer of LN-derived B2-B cells or purified CD21(hi)CD23(hi)CD24(hi) B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-B-reg subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease.
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| 54. |
- Yang, Jian, et al.
(författare)
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Genomic inflation factors under polygenic inheritance
- 2011
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 19:7, s. 807-812
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Tidskriftsartikel (refereegranskat)abstract
- Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.
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