Metabolism of innate immune cells: impact on atherosclerosis

Riksen, Niels P.; Stienstra, Rinke

doi:10.1097/mol.0000000000000539

Cited by 23 publications

(30 citation statements)

References 59 publications

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“…The involved intracellular mechanisms of atherogenesis include activation of signaling such as IL-1 and GM-CSF pathways, modulation of cellular metabolism such as glycolysis, cholesterol metabolism, fatty acid synthesis, and amino acid metabolism, as well as reprogramming of various epigenetic signatures. For a detailed overview of these mechanisms controlling innate immune activation in relation to atherosclerosis, we refer to some excellent recent reviews (4,(75)(76)(77). Of note, these pro-atherogenic signaling, metabolic, and epigenetic events are also involved in the induction of trained immunity.…”

Section: Trained Immunity Is Mechanistically Linked To Atherosclerosismentioning

confidence: 99%

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

et al. 2020

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Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis.

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Section: Trained Immunity Is Mechanistically Linked To Atherosclerosismentioning

confidence: 99%

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

et al. 2020

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“…The numbers of macrophages and monocytes present in the subendothelial intima of unaffected human arteries are not high, accounting for only 3-5% of total cell population. Since the arterial intima is the main site of foam cell formation, vascular smooth muscle a-actin (SMA)-positive resident cells (typical smooth muscle cells and pericyte-like cells) came into focus [20,21]. Recent studies clearly linked the SMA-positive cells with both foam cells formation and lipid accumulation, indicating that pericytes may be the leading source of foam cells [22,23].…”

Section: The Origin Of Foam Cellsmentioning

confidence: 99%

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Poznyak

Melnichenko

et al. 2020

Cells

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Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

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“…In recent years it has become clear that the development of atherosclerosis coincides with marked metabolic cellular alterations (Ali et al, 2018;Riksen and Stienstra, 2018). Particularly, inflammatory stimuli modify the intracellular metabolism of multiple cell types involved in atherogenesis, such as macrophages and endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…Particularly, inflammatory stimuli modify the intracellular metabolism of multiple cell types involved in atherogenesis, such as macrophages and endothelial cells. These cells are highly dependent on glycolysis for their energy metabolism to regulate cellular function (Bekkering et al, 2018;Riksen and Stienstra, 2018;Schnitzler et al, 2020). This induction in glycolysis could already be observed at regions where the endothelium is subjected to disturbed shear stress, making these early lesions susceptible for endothelial activation by lipoproteins, such as low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] (Libby, 2012;Schnitzler et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

Poels

Schnitzler

Waissi

et al. 2020

Front. Cell Dev. Biol.

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Aims 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158. Methods and Results PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6–8 weeks old male Ldlr –/– mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization. Conclusion High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis.

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Metabolism of innate immune cells: impact on atherosclerosis

Abstract: A pro-atherosclerotic environment reprograms the metabolism of myeloid cells in the various developmental phases of atherosclerosis. Knowledge of these metabolic programs facilitates the development of novel drugs to prevent atherosclerotic cardiovascular disease.

Cited by 23 publications

References 59 publications

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

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