Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126690 | GEO | 2020/02/18
REPOSITORIES: GEO
Similar Datasets
Project description:Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.
2021-03-05 | MTBLS2159 | MetaboLights
Project description:Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques
| PRJNA522993 | ENA
Project description:Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation in vitro. Next, we assessed endotoxin-induced peritonitis in myeloid-specific Acly-deficient mice and show that, apart from increased splenic Il6 expression, systemic and local inflammation were not affected by Acly deficiency. Also during obesity, both chronic low-grade inflammation and whole-body metabolic homeostasis remained largely unaltered in mice with Acly-deficient myeloid cells. Lastly, we show that macrophage-specific Acly deletion did not affect the severity of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. These results indicate that, despite increasing inflammatory responses in vitro, macrophage Acly deficiency does not worsen acute and chronic inflammatory responses in vivo. Together with our earlier observation that myeloid Acly deletion stabilizes atherosclerotic lesions, our findings highlight that therapeutic targeting of macrophage Acly can be beneficial in some, but not all, inflammatory disorders.
2021-04-19 | GSE169189 | GEO
Project description:Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with a potential anti-tumor phenotype in vivo, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.
2021-06-30 | GSE169187 | GEO
Project description:Recent studies suggest the presence of both âclassically activatedâ M1 and âalternatively activatedâ M2 macrophages in human atherosclerotic tissue, yet due to the lack of validated markers the reported localization patterns of these macrophage phenotypes within plaques are ambiguous. In the present study, we searched for markers that indisputably can identify differentiated M1 and M2 macrophages independently of stimuli that affect the activation status of the two subpopulations. We used these validated markers to assess the presence of M1 and M2 macrophages in different zones of human carotid artery atherosclerotic plaques obtained from 12 patients. Using microarray and qPCR technology we show that the frequently used macrophage subpopulation markers MCP-1 and CD206 do not discriminate between M1 and M2 macrophages. However, we confirm the subtype specificity of the classical M2 marker CD163 and we report that the genes INHBA and DSP (both M1) and SEPP1 and MARCKS (both M2) are highly suitable for macrophage phenotyping. mRNA expression of the pan-macrophage marker CD68 in the shoulder zones of the plaques and in adjacent tissue segments correlated positively with mRNA expression levels of SEPP1, MARCKS and CD163 (r=0.86, 0.94 and 0.96, and r= 0.86, 0.98 and 0.69, respectively) but not with the expression of the M1 markers DSP and INHBA. In contrast, mRNA expression of CD68 in the core of the plaques correlated positively with expression of DSP and INHBA (r=0.73 and 0.49) but not with SEPP1, MARCKS and CD163. These findings suggest that M1 macrophages predominate in the core of human carotid atherosclerotic plaques while M2 macrophages prevail at the periphery of the plaque. Keywords: Expression profiling by array Monocytes from healthy volunteers were differentiated into M1 and M2 macrophages by incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), respectively. After 5 days cells were exposed to oxidized LDL. Total RNA was isolated and subjected to gene expression profiling.
2016-06-01 | E-GEOD-22543 | biostudies-arrayexpress
Project description:Objective: Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. A cell-specific approach has the potential to address the question of gene expression differences between particular cell types in stable and unstable plaques with greater precision than approaches based on the study of whole plaques. Using laser micro-dissection, we isolated total RNA from macrophage-rich regions of stable and ruptured human atheromatous plaques derived from carotid endarterectomy samples which were comprehensively characterized using clinical, radiological and histological criteria, and carried out genome-wide gene expression profiling using microarrays. Results: The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p<0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p=5.4x10-7). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p=0.0086) and five-fold (p=0.0012) greater expression respectively in macrophages from ruptured plaques. Conclusions: We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential. Methods: We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Total RNA were subjected to two cycles of linear amplification. Transcriptional profiling was performed using Affymetrix HG-U133 plus 2.0 GeneChip arrays.
2012-12-31 | E-GEOD-41571 | biostudies-arrayexpress
Project description:Recent studies suggest the presence of both “classically activated” M1 and “alternatively activated” M2 macrophages in human atherosclerotic tissue, yet due to the lack of validated markers the reported localization patterns of these macrophage phenotypes within plaques are ambiguous. In the present study, we searched for markers that indisputably can identify differentiated M1 and M2 macrophages independently of stimuli that affect the activation status of the two subpopulations. We used these validated markers to assess the presence of M1 and M2 macrophages in different zones of human carotid artery atherosclerotic plaques obtained from 12 patients. Using microarray and qPCR technology we show that the frequently used macrophage subpopulation markers MCP-1 and CD206 do not discriminate between M1 and M2 macrophages. However, we confirm the subtype specificity of the classical M2 marker CD163 and we report that the genes INHBA and DSP (both M1) and SEPP1 and MARCKS (both M2) are highly suitable for macrophage phenotyping. mRNA expression of the pan-macrophage marker CD68 in the shoulder zones of the plaques and in adjacent tissue segments correlated positively with mRNA expression levels of SEPP1, MARCKS and CD163 (r=0.86, 0.94 and 0.96, and r= 0.86, 0.98 and 0.69, respectively) but not with the expression of the M1 markers DSP and INHBA. In contrast, mRNA expression of CD68 in the core of the plaques correlated positively with expression of DSP and INHBA (r=0.73 and 0.49) but not with SEPP1, MARCKS and CD163. These findings suggest that M1 macrophages predominate in the core of human carotid atherosclerotic plaques while M2 macrophages prevail at the periphery of the plaque. Keywords: Expression profiling by array
2016-06-01 | GSE22543 | GEO
Project description:Differentiation of cardiac fibroblasts (CFs) to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting the myofibroblast gene program. Here, we investigated the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast formation and persistence in cardiac fibrosis. Inactivation of ACLY prevented, and importantly reversed, myofibroblasts towards quiescence. Genetic deletion of Acly in activated myofibroblasts prevented fibrosis and preserved cardiac function in murine pressure-overload. TGFβ stimulation enhanced ACLY nuclear localization and increased H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of dominant-negative ACLY mutant prevented myofibroblast formation and H3K27ac. Our data indicate nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide novel clinical rational to prevent and reverse pathological fibrosis. CUT&RUN Sequencing for H3K27ac on the role of ACLY in myofibroblast differentiaton.
2024-05-16 | GSE232010 | GEO
Project description:Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary circulations, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, known for its involvement in de novo lipid synthesis and histone acetylation, emerges as a key regulator in sustaining vascular smooth muscle cell proliferation and survival. Utilizing rare human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured vascular smooth muscle cells, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation. In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrate its efficacy in mitigating systemic vascular remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target. Human ex-vivo tissue culture further supports our findings, showcasing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified "multiple-hit" therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions.
2024-11-14 | GSE254952 | GEO
Project description:We used single cell RNA-sequencing of aortic CD45+ cells, combined with immunohistologic, morphometric and flow cytometric analyses to define the changes in plaque immune cell composition, gene expression and function following miR-33 inhibition. We report that anti-miR-33 treatment of Ldlr–/– mice with advanced atherosclerosis reduced plaque burden and altered the plaque immune cell landscape by shifting the balance of pro- and anti-atherosclerotic macrophage and T cell subsets. By quantifying the kinetic processes that determine plaque macrophage burden, we found that anti-miR-33 reduced levels of circulating monocytes and splenic myeloid progenitors, decreased macrophage proliferation and retention, and promoted macrophage attrition by apoptosis and efferocytotic clearance. scRNA-sequencing of aortic arch plaques showed that anti-miR-33 reduced the frequency of MHCIIhi “inflammatory” and Trem2hi “metabolic” macrophages, but not tissue resident macrophages. Furthermore, anti-miR-33 led to derepression of distinct miR-33 target genes in the different macrophage subsets: in resident and Trem2hi macrophages, anti-miR-33 relieved repression of miR-33 target genes involved in lipid metabolism (e.g., Abca1, Ncoa1, Ncoa2, Crot), whereas in MHCIIhi macrophages, anti-miR-33 upregulated target genes involved in chromatin remodeling and transcriptional regulation. Anti-miR-33 also reduced the accumulation of aortic CD8+ and CD4+ Th1 cells, and increased levels of FoxP3+ regulatory T cells in plaques, consistent with an immune-dampening effect on plaque inflammation.
2021-04-21 | GSE161494 | GEO