Treatment with Statins Does Not Revert Trained Immunity in Patients with Familial Hypercholesterolemia

Bekkering, Siroon; Stiekema, Lotte C.A.; Moens, Sophie Bernelot; Verweij, Simone L.; Novakovic, Boris; Prange, K.H.M.; Versloot, Miranda; Lennep, Jeanine E. Roeters van; Stunnenberg, Henk; Winther, Menno P.J. de; Stroes, Erik S.G.; Joosten, Leo A. B.; Netea, Mihai G.; Riksen, Niels P.

doi:10.1016/j.cmet.2019.05.014

Cited by 111 publications

(98 citation statements)

References 11 publications

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“…This trained immunity phenotype persisted even after the mice had been switched to a standard chow diet for another 4 weeks, despite circulating cholesterol levels and systemic inflammatory markers returning to normal 8 . Several small proof-of-principle studies in patients suggest that trained immunity also occurs in the setting of dyslipoproteinaemia: monocytes from patients with familial hypercholesterolaemia are characterized by an enhanced cytokine production capacity and enrichment of H3K4me3 on their promoters, which remains present even after 3 months of cholesterol-lowering statin treatment 148 . Furthermore, circulating monocytes from patients with severe coronary artery atherosclerosis exhibit a trained immune phenotype in terms of enhanced cytokine production capacity and glycolytic metabolism and epigenetic reprogramming at the level of histone methylation 149,150 .…”

Section: Pathological Outcomes Of Trained Immunitymentioning

confidence: 99%

Defining trained immunity and its role in health and disease

et al. 2020

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| Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity. ✉

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Section: Pathological Outcomes Of Trained Immunitymentioning

confidence: 99%

Defining trained immunity and its role in health and disease

et al. 2020

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“…Glutaminolysis represents another metabolic reconfiguration observed in immune training of cells with β‐glucan, and inhibition of this metabolic shift leads to reduced induction of trained immunity in vivo . Similarly altered immune states with enhanced inflammatory cytokine production associated with epigenetic modifications have not only been observed in settings using microbial stimulations, but also in response to sterile ligands such as oxLDL or hypercholesterolemia in the context of atherosclerosis …”

Section: The Innate Immune System and Innate Immune Memorymentioning

confidence: 99%

“…33 Similarly altered immune states with enhanced inflammatory cytokine production associated with epigenetic modifications have not only been observed in settings using microbial stimulations, but also in response to sterile ligands such as oxLDL or hypercholesterolemia in the context of atherosclerosis. 34,35…”

Section: The Innate Immune Sys Tem and Innate Immune Memorymentioning

confidence: 99%

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

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et al. 2019

Immunological Reviews

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Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage‐associated molecules leading to an enhanced non‐specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low‐grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long‐term systemic inflammation seen in gout. We revisit existing evidence for urate‐induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.

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“…63,65 A recent prospective cohort study demonstrated that monocytes derived from patients with familial hypercholesterolaemia displayed the trained immune phenotype compared to healthy controls. 67 Interestingly, this effect was not ablated following 3 months of statin treatment. 68 The use of statins to abolish this effect is complicated as blocking cholesterol synthesis in the HSPCs would likely also induce the expression of the low-density lipoprotein receptor (LDLr), an important cholesterol uptake pathway in HSPCs, providing an alternative source of lipid for the cell (i.e.…”

Section: Sterolsmentioning

confidence: 98%

“…Lowering cholesterol levels by blocking 3‐hydroxy‐3‐methylglutaryl (HMG)‐CoA reductase through statins reversed the enhanced myelopoiesis observed in β‐glucan treatment, presumably by preventing lipid raft formation and the expression of CD131, while also preventing cytokine production after restimulation . A recent prospective cohort study demonstrated that monocytes derived from patients with familial hypercholesterolaemia displayed the trained immune phenotype compared to healthy controls . Interestingly, this effect was not ablated following 3 months of statin treatment .…”

Section: Lipid Metabolism In Haematopoiesismentioning

confidence: 99%

Fat for fuel: lipid metabolism in haematopoiesis

et al. 2019

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The importance of metabolic regulation in the immune system has launched back into the limelight in recent years. Various metabolic pathways have been examined in the context of their contribution to maintaining immune cell homeostasis and function. Moreover, this regulation is also important in the immune cell precursors, where metabolism controls their maintenance and cell fate. This review will discuss lipid metabolism in the context of haematopoiesis, that is blood cell development. We specifically focus on nonoxidative lipid metabolism which encapsulates the synthesis and degradation of the major lipid classes such as phospholipids, sphingolipids and sterols. We will also discuss how these metabolic processes are affected by haematological malignancies such as leukaemia and lymphoma, which are known to have altered metabolism, and how these different pathways contribute to the pathology.

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Treatment with Statins Does Not Revert Trained Immunity in Patients with Familial Hypercholesterolemia

Cited by 111 publications

References 11 publications

Defining trained immunity and its role in health and disease

Defining trained immunity and its role in health and disease

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

Fat for fuel: lipid metabolism in haematopoiesis

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