Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo

Bekkering, Siroon; Munckhof, Inge van den; Nielen, Tim Mj; Lamfers, E. J. P.; Dinarello, Charles A.; Rutten, Joost H.W.; Graaf, Jacqueline de; Joosten, Leo A. B.; Netea, Mihai G.; Gomes, Marc E.; Riksen, Niels P.

doi:10.1016/j.atherosclerosis.2016.10.019

Cited by 174 publications

(165 citation statements)

References 27 publications

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“…To further elucidate the role of trained immunity in the development of these disorders, we assessed the inflammatory phenotype of monocytes isolated from patients with severe symptomatic coronary atherosclerosis. We demonstrated that monocytes from patients with symptomatic carotid atherosclerosis show an increased production of IL‐1β upon ex vivo stimulation with LPS for 24 hours compared to controls . Baseline RNA expression of IL‐1β and IL‐1RA was significantly higher in these patients compared to controls.…”

Section: The Role Of Il‐1 In Trained Immunitymentioning

confidence: 80%

“…Similar to β‐glucan‐ and BCG‐induced trained monocytes, glycolysis was shown to be increased in symptomatic CAD patients. Interestingly, the expression levels of IL‐1β significantly correlated with the expression of the two rate limiting enzymes in the glycolysis pathway, hexokinase 2 (HK2) and 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) . Since many clinical as well as experimental studies have shown that IL‐1β plays a key role in the progression of atherosclerosis, the enhanced production of IL‐1 as a result of trained innate immunity programs might be an important process contributing to the development of atherosclerosis.…”

Section: The Role Of Il‐1 In Trained Immunitymentioning

confidence: 99%

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The role of the interleukin‐1 family in trained immunity

Moorlag

Röring

Joosten

et al. 2017

Immunological Reviews

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101

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Immunological memory was long considered a trait exclusive to cells of the adaptive immune system. However, recent studies have shown that after activation of the innate immune system, innate immune cells may undergo long-term functional reprogramming characterized by the ability to mount either a stronger or attenuated inflammatory response upon reactivation. This phenomenon, which has been termed trained immunity and is a de facto innate immune memory, is regulated by a network of integrated metabolic and epigenetic rewiring. The endogenous mediators that modulate trained immunity in the host are only partially understood, but increasing evidence supports the concept that the interleukin (IL)-1 family of cytokines plays an important role. In this review, we will highlight key findings from studies that provide insight into the multifaceted roles of members of the IL-1 family for trained immunity. Finally, we will discuss how the recent advances of our understanding on the role of IL-1 cytokines in this field may lead to new therapeutic strategies for treatment of common conditions, such as IL-1-driven autoinflammatory diseases.

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Section: The Role Of Il‐1 In Trained Immunitymentioning

confidence: 80%

Section: The Role Of Il‐1 In Trained Immunitymentioning

confidence: 99%

The role of the interleukin‐1 family in trained immunity

Moorlag

Röring

Joosten

et al. 2017

Immunological Reviews

Self Cite

101

View full text Add to dashboard Cite

show abstract

“…A similar finding has been found by comparing monocytes from subjects with symptomatic vs . asymptomatic carotid atherosclerosis (Bekkering et al, 2016). Another study shows that HDAC3 inhibitors increase the expression of ABCA1 and ABCG1 in cultured macrophages and that myeloid deletion of HDAC3 in Western diet-fed Ldlr -/- mice suppresses atherosclerosis and promotes a more resolving phenotype in lesional macrophages (Hoeksema et al, 2014).…”

Section: Inflammatory Macrophages Drive Atherosclerosis Progressionmentioning

confidence: 99%

“…Another challenge to treating chronic autoimmune diseases is the accumulation of autoreactive tissue resident memory lymphocytes whose pathogenic phenotypes are stabilized by epigenetic modifications of various gene loci (Phan et al, 2017). There is also evidence that metabolic conditions can induce epigenetic changes in macrophages, leading to a form of innate immune memory (“trained immunity”) (Netea et al, 2016; Phan et al, 2017) that may promote lesion progression (Bekkering et al, 2016). In this regard, pre-clinical studies have provided support for the principal that targeting physiologic epigenetic modifiers, for example with inhibitors of Bromodomain and Extra-Terminal motif (BET) proteins, can inhibit inflammatory gene expression and reduce atherosclerosis (Brown et al, 2014; Jahagirdar et al, 2014).…”

Section: Summary and Therapeutic Considerationsmentioning

confidence: 99%

Monocyte-Macrophages and T Cells in Atherosclerosis

2017

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Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein B-lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving, leading to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis through monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance of regulatory vs. effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in regulating these responses. Herein we review select topics that shed light on these processes and suggest new treatment strategies.

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“…Molecular and cellular mechanisms involved in this phenomenon are still not fully understood. It is believed that the main mechanism underlying enhanced responses involves epigenetic reprogramming, which in turn may entail altered pattern recognition receptors’ expression, metabolic reprogramming, or/and altered cytokines release (Saeed et al, 2014; Bekkering et al, 2016b). Long-term epigenetic changes in monocytes and macrophages apparently involve both histone methylation and acetylation, as for instance H3K4 monomethylation and H3K27 acetylation induced by LPS (Ostuni et al, 2013; Saeed et al, 2014), and histone H3K4 trimethylation and H3K27 acetylation caused by β-glucan (Quintin et al, 2012; Saeed et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Different Regulation of Interleukin-1 Production and Activity in Monocytes and Macrophages: Innate Memory as an Endogenous Mechanism of IL-1 Inhibition

et al. 2017

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Production and activity of interleukin (IL)-1β are kept under strict control in our body, because of its powerful inflammation-promoting capacity. Control of IL-1β production and activity allows IL-1 to exert its defensive activities without causing extensive tissue damage. Monocytes are the major producers of IL-1β during inflammation, but they are also able to produce significant amounts of IL-1 inhibitors such as IL-1Ra and the soluble form of the decoy receptor IL-1R2, in an auto-regulatory feedback loop. Here, we investigated how innate immune memory could modulate production and activity of IL-1β by human primary monocytes and monocyte-derived tissue-like/deactivated macrophages in vitro. Cells were exposed to Gram-negative (Escherichia coli) and Gram-positive (Lactobacillus acidophilus) bacteria for 24 h, then allowed to rest, and then re-challenged with the same stimuli. The presence of biologically active IL-1β in cell supernatants was calculated as the ratio between free IL-1β (i.e., the cytokine that is not bound/inhibited by sIL-1R2) and its receptor antagonist IL-1Ra. As expected, we observed that the responsiveness of tissue-like/deactivated macrophages to bacterial stimuli was lower than that of monocytes. After resting and re-stimulation, a memory effect was evident for the production of inflammatory cytokines, whereas production of alarm signals (chemokines) was minimally affected. We observed a high variability in the innate memory response among individual donors. This is expected since innate memory largely depends on the previous history of exposure or infections, which is different in different subjects. Overall, innate memory appeared to limit the amount of active IL-1β produced by macrophages in response to a bacterial challenge, while enhancing the responsiveness of monocytes. The functional re-programming of mononuclear phagocytes through modulation of innate memory may provide innovative approaches in the management of inflammatory diseases, as well as in the design of new immunization strategies. In this respect, the interindividual variability in innate memory suggests the need of a personalized assessment.

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Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo

Abstract: Circulating monocytes of patients with symptomatic, but not asymptomatic, atherosclerosis have a pro-inflammatory phenotype and increased expression of glycolytic enzymes, associated with epigenetic remodeling at the level of histone methylation.

Cited by 174 publications

References 27 publications

The role of the interleukin‐1 family in trained immunity

The role of the interleukin‐1 family in trained immunity

Monocyte-Macrophages and T Cells in Atherosclerosis

Different Regulation of Interleukin-1 Production and Activity in Monocytes and Macrophages: Innate Memory as an Endogenous Mechanism of IL-1 Inhibition

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