Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR-/- mice

Boshuizen, Margit; Neele, Annette E.; Gijbels, Marion J.J.; Velden, Saskia van der; Hoeksema, Marten A.; Forman, Ruth; Müller, Werner; Bossche, Jan Van den; Winther, Menno P.J. de

doi:10.1016/j.atherosclerosis.2016.01.026

Cited by 7 publications

(4 citation statements)

References 35 publications

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“…These findings suggest that the proatherogenic actions of IFNγ on macrophages may be independent of its canonical signaling pathway, which is supported by previous studies showing that myeloid cell deletion of Stat1 or Ifngr2 , two key components of this signaling pathway ( Ikushima et al, 2013 ), failed to attenuate atherogenesis ( Boshuizen et al, 2016 ; Lim et al, 2008 ). Consistent with this hypothesis, previous studies showed that IFNγ alters expression of many genes in Stat1 −/− macrophages ( Gil et al, 2001 ), suggesting that STAT1-independent mechanisms significantly contribute to the effects of this cytokine on macrophage gene expression and function.…”

Section: Discussionsupporting

confidence: 77%

Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network

et al. 2018

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SUMMARY Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic “macrophage-sterol-responsive-network” (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor (Ifngr1−/−) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr−/− mice with obesity/IR, but does not affect these parameters in Ldlr−/− mice without obesity/IR. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis.

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Section: Discussionsupporting

confidence: 77%

Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network

et al. 2018

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“…16 However, other reports suggest that myeloid IFNγ receptor 2 deficiency does not affect atherosclerosis in hyperlipidemic mice. 17 Such contradictory observations prompted us to examine the single-cell responses to IFNγ signaling in the atherosclerosis context. Several studies demonstrated that transcriptional heterogeneity and immune cell function may affect atherosclerosis outcomes.…”

Section: Clinical Perspectivementioning

confidence: 99%

Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug–Gene Networks: From Biology to Precision Therapeutics

Decano,

Maiorino,

Matamalas

et al. 2023

Circulation

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BACKGROUND: Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions. METHODS: Primary human macrophages activated by IFNγ (M[IFNγ]) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis. RESULTS: Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M[IFNγ] i ) and phagocytic (M[IFNγ] p ). M(IFNγ) i had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ) p . M(IFNγ) p were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ) i . Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ) i subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ) i subpopulation while expanding the M(IFNγ) p subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification. CONCLUSIONS: We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.

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“…Another macrophages population expressed canonical M1 (Cd11c, Ccl2 and Il-1β) or M2 (Mrc1, Clec10a and Mgl2) markers. Surprisingly, there are more expression M2-marker resident macrophage populations in the plaque in comparison to M1-marker populations, maybe due to low IL-4 and IL-13 levels in the plaque [ 42 ], but not associated with IFN-γ and its receptor [ 43 ]. This phenomenon is very interesting, because anti-inflammation therapy, such as CANTOS clinical trial, using anti-IL-1β antibody-canakinumab, significantly reduced recurrent cardiovascular events independent of lipid-lowering [ 44 ].…”

Section: Intraplaque Cell Types and Interactions In Plaque Stabilitymentioning

confidence: 99%

The Role of Hydrogen Sulfide in Plaque Stability

Lin

Geng

2022

Antioxidants

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Atherosclerosis is the greatest contributor to cardiovascular events and is involved in the majority of deaths worldwide. Plaque rapture or erosion precipitates life-threatening thrombi, resulting in the obstruction blood flow to the heart (acute coronary syndrome), brain (ischemic stroke) or low extremities (peripheral vascular diseases). Among these events, major causation dues to the plaque rupture. Although the initiation, procession, and precise time of controlling plaque rupture are unclear, foam cell formation and apoptosis, cell death, extracellular matrix components, protease expression and activity, local inflammation, intraplaque hemorrhage, and calcification contribute to the plaque instability. These alterations tightly associate with the function regulation of intraplaque various cell populations. Hydrogen sulfide (H2S) is gasotransmitter derived from methionine metabolism and exerts a protective role in the genesis of atherosclerosis. Recent progress also showed H2S mediated the plaque stability. In this review, we discuss the progress of endogenous H2S modulation on functions of vascular smooth muscle cells, monocytes/macrophages, and T cells, and the molecular mechanism in plaque stability.

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Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR-/- mice

Cited by 7 publications

References 35 publications

Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network

Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network

Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug–Gene Networks: From Biology to Precision Therapeutics

The Role of Hydrogen Sulfide in Plaque Stability

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