NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis (original) (raw)
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2016
Rationale: NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Objective: Nur77 regulates the development of monocytes, particularly patrolling Ly6C monocytes that may be involved in resolution of inflammation. We sought to determine how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Methods and Results: Nur77/ chimeric mice on a Ldlr/ background showed a 3-fold increase in athero-sclerosis development when fed a Western diet for 20 weeks, despite having a drastic reduction in Ly6C patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoE/Nur77/) also showed increased atherosclerosis after 11 weeks of Western diet. Atherosclerosis was associated with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objective-Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages. Methods and Results-Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor ␣. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1 and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1␣ and -1 and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized-low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation.
Nuclear receptor control of opposing macrophage phenotypes in cardiovascular disease
Frontiers in Bioscience, 2012
Introduction 3. Nuclear receptor control of macrophage activation 3.1. Regulation of macrophage activation by PPARs 3.2. Mineralocorticoid receptor activates proinflammatory macrophage function 3.3. Interaction of nuclear receptors and cytokines 4. Alternatively activated macrophage phenotypes in cardiovascular disease 4.1. Cardiac inflammation, hypertrophy and fibrosis 4.2. Atherosclerosis 4.3. Stroke 5. Heme oxygenase-1 in alternatively activated macrophages 5.1. Atherosclerosis 5.2. Alveolar macrophages and pulmonary hypertension 6. Strategies to study macrophage polarization in disease 7. Summary and perspectives 8. Acknowledgements 9. References
Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature
European Heart Journal, 2019
Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerot...
Circulation, 2012
Background-Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. Methods and Results-We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe Ϫ/Ϫ mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C hi inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. Conclusions-These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy. (Circulation. 2012;126:952-962.)
R Innate immunity and monocyte-macrophage activation in atherosclerosis
Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2007
To develop a murine model system to test the role of monocyte-derived macrophages in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colonystimulating factor gene was bred onto the apolipoprotein E (apoE)-deficient background. The doubly mutant (op/apoEdeficient) mice fed a low-fat chow diet had significantly smaller proximal aortic lesions at an earlier stage of progression than their apoE-deficient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also had decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of 41300 mg/dl. Statistical analysis determined that atherosclerosis lesion area was significantly affected by the op genotype and gender. The confounding variables of body weight, plasma cholesterol, and monocyte differential, which were all affected by op genotype, had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR) Ϫ/Ϫ mice. SR-AI/II-deficient (SR-AI/II Ϫ/Ϫ ) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II Ϫ/Ϫ and SR-AI/II ϩ/ϩ mice, whereas both female and male SR-AI/II Ϫ/Ϫ mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR Ϫ/Ϫ mice were reconstituted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II Ϫ/Ϫ 3 C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ 3 C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice compared with SR-AI/II ϩ/ϩ 3 LDLR Ϫ/Ϫ mice. These results demonstrate in vivo that SR-AI/II expression has no impact on plasma lipid levels and that macrophage SR-AI/II contributes significantly to atherosclerotic lesion formation. (Arterioscler Thromb Vasc
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
Macrophage-derived foam cells play an important role in the initiation and progression of atherosclerosis. To examine the role of the macrophage low density lipoprotein receptor (LDLr) in atherosclerotic lesion formation, bone marrow from LDLr knockout [LDLr(Ϫ/Ϫ)] mice was transplanted into irradiated wild-type C57Bl/6 [LDLr(ϩ/ϩ)] mice. After 3 months on an atherogenic diet, C57Bl/6 mice, reconstituted with LDLr(Ϫ/Ϫ) bone marrow, showed a mean lesion area of 34.7ϫ10 3 Ϯ22.4x10 3 m 2 compared with 100.8ϫ10 3 Ϯ33.0ϫ10 3 m 2 (PϽ0.001) in control C57Bl/6 mice that were transplanted with LDLr(ϩ/ϩ) bone marrow. There were no significant differences in total serum cholesterol, triglyceride levels, and lipoprotein profiles between the 2 groups. Histochemical analysis of macrophage LDLr expression in the atherosclerotic lesions indicated that C57Bl/6 mice, reconstituted with LDLr(ϩ/ϩ) bone marrow, showed extensive staining of the foam cells in the atherosclerotic lesions, whereas mice reconstituted with LDLr(Ϫ/Ϫ) bone marrow showed only a few LDLr-positive foam cells. In vitro, peritoneal macrophages isolated from wild-type C57Bl/6 mice were, respectively, 4.7-and 10.7-fold more effective in cell association and degradation of atherogenic 125 I--very low density lipoprotein than were LDLr(Ϫ/Ϫ) peritoneal macrophages, establishing that the LDLr on macrophages is important for the interaction of macrophages with -very low density lipoprotein. It is concluded that the LDLr on macrophages can facilitate the development of atherosclerosis, possibly by mediating the uptake of atherogenic lipoproteins. (Arterioscler Thromb Vasc