Cholesterol crystals drive metabolic reprogramming and M1 macrophage polarisation in primary human macrophages

O'Rourke, Sinead A; Neto, Nuno; Devilly, Eimear; Shanley, Lianne C.; Fitzgerald, Hannah K.; Monaghan, Michael G.; Dunne, Aisling

doi:10.1016/j.atherosclerosis.2022.05.015

Cited by 24 publications

(10 citation statements)

References 50 publications

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“…64 Indeed, it is worth noting that such findings extend beyond the joint, and we recently demonstrated that atherosclerosis-associated cholesterol crystals can alter macrophage bioenergetics by increasing the glycolytic profile of the cell. 65 This in vitro effect was dependent on the glycolytic enzyme, pyruvate kinase isoenzyme type M2 (PKM2), and supports a recent in vivo study demonstrating that inhibition of PKM2 nuclear translocation reduces glycolytic rate while also suppressing atherosclerosis and inflammation in Ldlr −/− mice. 66 Taken together, these studies reveal potential new targets to limit inflammation and macrophage polarization by modulating the metabolic state of pathogenic immune cells.…”

Section: Endogenous Drivers Of Metabolic Reprogrammingsupporting

confidence: 81%

Endogenous drivers of altered immune cell metabolism

Shanley

Fitzgerald

O'Rourke

et al. 2022

Exp Biol Med (Maywood)

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Dysregulated metabolism has long been recognized as a feature of many metabolic disorders. However, recent studies demonstrating that metabolic reprogramming occurs in immune cells have led to a growing interest in the relationship between metabolic rewiring and immune-mediated disease pathogeneses. It is clear now that immune cell subsets engage in different metabolic pathways depending on their activation and/or maturation state. As a result, it may be possible to modulate metabolic reprogramming for clinical benefit. In this review, we provide an overview of immune cell metabolism with focus on endogenous drivers of metabolic reprogramming given their link to a number of immune-mediated disorders.

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Section: Endogenous Drivers Of Metabolic Reprogrammingsupporting

confidence: 81%

Endogenous drivers of altered immune cell metabolism

Shanley

Fitzgerald

O'Rourke

et al. 2022

Exp Biol Med (Maywood)

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“…Metabolic overloads due to cholesterol uptake affect macrophage structure and functions, including their morphological extension, macrophage polarization (M1-like or M2-like), and efferocytosis. 15 16 Hypercholesterolaemia is responsible for cholesterol-laden macrophages, with cholesterol promoting the pro-inflammatory M1 phenotype in a glycolysis-dependent manner. 15 16 Autophagy plays an important role in regulating intracellular lipid droplets and lipid metabolism, 17 and controlling immune responses.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Enhancers Regulate Cholesterol-Induced Cytokine Secretion and Cytotoxicity in Macrophages

Lee

Kam

Cheon

2023

J Lipid Atheroscler

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Objective Hypercholesterolaemia transforms macrophages into lipid-laden foam cells in circulation, which can activate the immune response. Compromised autophagy and inflammatory cytokines are involved in the pathogenesis and progression of metabolic diseases. The aim of this study was to identify the role of autophagy as a modulator of the inflammatory response and cytotoxicity in macrophages under hypercholesterolaemic conditions. Methods High cholesterol-induced cytokine secretion and alteration of autophagy-associated molecules were confirmed by cytokine array and western blot analysis, respectively. To confirm whether autophagic regulation affects high cholesterol-induced cytokine release and cytotoxicity, protein levels of autophagic molecules, cell viability, and cytotoxicity were measured in cultured macrophages treated autophagy enhancers. Results Cholesterol treatment increased cytokine secretion, cellular toxicity, and lactate dehydrogenase release in lipopolysaccharide (LPS)-primed macrophages. Concomitantly, altered levels of autophagy-related molecules were detected in LPS-primed macrophages under hypercholesterolaemic conditions. Treatment with autophagy enhancers reversed the secretion of cytokines, abnormally expressed autophagy-associated molecules, and cytotoxicity of LPS-primed macrophages. Conclusion Autophagy enhancers inhibit inflammatory cytokine secretion and reduce cytotoxicity under metabolic disturbances, such as hypercholesterolaemia. Modulation of autophagy may be a novel approach to control the inflammatory response observed in metabolic diseases.

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“…In the present study we found macrophage-related differential genes were mostly enriched in osteoclast differentiation, B cell receptor signaling pathways, IL-17 signaling pathways, fluid shear stress and atherosclerosis, primary bile acid biosynthesis, and PPAR signaling pathways. Subsequent subgrouping of macrophages and pseudo-chronological analysis showed that when normal tissues developed into atherosclerotic ones, CCL13 monocytes evolved into C1QB, APOBEC3A, and FABP4 monocytes of the M2 phenotype ( 37 , 38 ). In addition, we found six transcription factors, MAF, MEF2C, IRF1, FOSB, NFIL3, and EGR1, were all reduced in atherosclerotic plaques compared to the surrounding normal vessels, which shows the number and strength of intercellular interactions are weakened when the vessels become atherosclerotic.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic, transcriptomic, and metabolomic characterization of human atherosclerosis

Liu¹,

Li²,

Yin³

et al. 2022

Ann Transl Med

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Background: Atherosclerosis is the main cause of many cardiovascular and cerebrovascular diseases (CVDs), and gaining a deeper understanding of the intercellular connections and key central genes which mediate formation of atherosclerotic plaques is required.Methods: We performed a comprehensive bioinformatics analysis of differential genetic screening, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway annotation, protein-protein interactions (PPIs), pseudo-timing, intercellular communication, transcription factors on carotid single-cell sequencing data, and aortic bulk transcriptome and metabolomic data.Results: Ten cell types were identified in the data: T cells, monocytes, smooth muscle cells, endothelial cells, B cells, fibroblasts, plasma cells, mast cells, dendritic cells, and natural killer cells. Endothelial, fibroblast, macrophage, and smooth muscle cell subtype differentiation trajectories, interaction networks, and important transcription factors were characterized in detail. Finally, using this information combined with transcriptome and metabolome analyses, we found the key genes and signaling pathways of atherosclerosis, especially the advanced glycation end products and receptor for advanced glycation end products signaling pathway (AGE-RAGE signaling pathway) in diabetic complications, linked the differential metabolites with fibroblasts and atherosclerosis and contributed to it in patients with diabetes.Conclusions: Collectively, this study provides key genes, signaling pathways, cellular communication, and transcription factors among endothelial cells, fibroblasts, macrophages, and smooth muscle cells for the study of atherosclerotic plaques, and provides a basis for the diagnosis and treatment of atherosclerosis-like sclerosis.

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Cholesterol crystals drive metabolic reprogramming and M1 macrophage polarisation in primary human macrophages

Cited by 24 publications

References 50 publications

Endogenous drivers of altered immune cell metabolism

Endogenous drivers of altered immune cell metabolism

Autophagy Enhancers Regulate Cholesterol-Induced Cytokine Secretion and Cytotoxicity in Macrophages

Single-cell transcriptomic, transcriptomic, and metabolomic characterization of human atherosclerosis

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