RATIONALE:There is strong epidemiological evidence for an association between acute and chronic infections and the occurrence of atherosclerotic cardiovascular disease. The underlying ...pathophysiological mechanisms remain unclear. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. It has recently been established that monocytes/macrophages can develop a long-lasting proinflammatory phenotype after brief stimulation with micro-organisms or microbial products, which has been termed trained immunity.
OBJECTIVE:The aim of this study is to assess whether trained immunity mediates the link between infections and atherosclerotic cardiovascular disease.
METHODS AND RESULTS:Brief exposure of monocytes to various micro-organisms results in the development of macrophages with a persistent proinflammatory phenotypethis represents a de facto nonspecific innate immune memory, which has been termed trained immunity. This is mediated by epigenetic reprogramming at the level of histone methylation and a profound rewiring of intracellular metabolism. Although this mechanism offers powerful protection against reinfection, trained macrophages display an atherogenic phenotype in terms of cytokine production and foam cell formation. Trained monocytes are present up to 3 months after experimental infection in humans. Moreover, a trained immunity phenotype is present in patients with established atherosclerosis.
CONCLUSIONS:We propose that trained immunity provides the missing mechanistic link that explains the association between infections and atherosclerosis. Therefore, pharmacological modulation of trained immunity has the potential to prevent infection-related atherosclerotic cardiovascular disease in the future.
Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. In recent years, however, this paradigm has shifted: Cells of the innate immune ...system appear to be able to gain memory characteristics after transient stimulation, resulting in an enhanced response upon secondary challenge. This phenomenon has been called trained immunity. Trained immunity is characterized by nonspecific increased responsiveness, mediated via extensive metabolic and epigenetic reprogramming. Trained immunity explains the heterologous effects of vaccines, which result in increased protection against secondary infections. However, in chronic inflammatory conditions, trained immunity can induce maladaptive effects and contribute to hyperinflammation and progression of cardiovascular disease, autoinflammatory syndromes, and neuroinflammation. In this review we summarize the current state of the field of trained immunity, its mechanisms, and its roles in both health and disease.
OBJECTIVE—Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported ...that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation.
APPROACH AND RESULTS—Isolated human monocytes were exposed for 24 hours to medium or oxLDL. After washing and resting for 6 days, the cells were exposed to toll-like receptor 2 and 4 agonists. Pre-exposure to oxLDL increased mRNA expression and protein formation on toll-like receptor 2 and 4 stimulation of several proatherogenic proteins, including interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9. In addition, foam cell formation was enhanced after oxLDL exposure, which was associated with an upregulation of scavenger receptors CD36 and scavenger receptor-A and downregulation of ATP-binding cassette transporters, ABCA1 and ABCG1. Chromatin immunoprecipitation performed 6 days after oxLDL stimulation demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of tnfα, il-6, il-18, mcp-1, mmp2, mmp9, cd36, and sr-a. Finally, pretreatment of the monocytes with the histone methyltransferase inhibitor methylthioadenosine completely prevented the oxLDL-induced long-lasting proinflammatory phenotype.
CONCLUSIONS—Brief exposure of monocytes to a low concentration of oxLDL induces a long-lasting proatherogenic macrophage phenotype via epigenetic histone modifications, characterized by increased proinflammatory cytokine production and foam cell formation.
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. ...Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.
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•Induction of trained immunity by β-glucan depends on intracellular mevalonate•Mevalonate induces trained immunity in human monocytes•Mevalonate-induced training is mediated through increased function of IGF1 receptor•Monocytes of HIDS patients (that accumulate mevalonate) have a trained phenotype
A metabolite is critical to train innate immune cells to develop long-term memory.
BACKGROUND:Elevated lipoprotein(a) Lp(a) is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is ...the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.
METHODS:In vivo imaging techniques including magnetic resonance imaging, F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.
RESULTS:We show that subjects with elevated Lp(a) (108 mg/dL 50–195 mg/dL; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL 2–28 mg/dL; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).
CONCLUSIONS:These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.
CLINICAL TRIAL REGISTRATION:URLhttp://www.trialregister.nl. Unique identifierNTR5006 (VIPER Study).
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through ...network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
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•Cellular metabolism undergoes major shifts in β-glucan-trained monocytes•Glucose, glutamine, and cholesterol metabolism are crucial in trained immunity•Accumulation of fumarate is essential for epigenetic changes in trained immunity
As part of the IHEC consortium, Arts et al. dissect how metabolic pathways regulate epigenetic rewiring in trained immunity (innate immune memory). They show that glycolysis, glutaminolysis, and cholesterol metabolism are indispensable in trained monocytes and link fumarate accumulation to epigenetic changes. Explore the Cell Press IHEC webportal at http://www.cell.com/consortium/IHEC.
Highlights • Innate immune cells can adopt a long-term activated phenotype after exposure to atherogenic stimuli. • This ‘trained’ phenotype is mediated by epigenetic remodeling and changes in ...intracellular immunometabolism. • Trained immunity contributes to the persistent pro-inflammatory milieu of atherosclerotic plaques. • Diet can have long lasting effects on innate immune function by microbiome-derived PAMPs and metabolites.
Sodium butyrate is well-known for its immune-modulatory properties. Studies until now only focused on the in vitro effects of butyrate or assessed local effects in the gut upon butyrate ...administration. In this trial, we studied the systemic anti-inflammatory effects induced by sodium butyrate supplementation in humans. Nine healthy (Lean) and ten obese (metabolic syndrome group, MetSyn) males were given 4 grams sodium butyrate daily for 4 weeks. PBMCs were isolated before and after supplementation for direct stimulation experiments and induction of trained immunity by oxidized low-density lipoprotein (oxLDL), β-glucan, or Bacillus Calmette-Guérin vaccine (BCG). Butyrate supplementation moderately affected some of the cytokine responses in the MetSyn group. In the direct stimulation setup, effects of butyrate supplementation were limited. Interestingly, butyrate supplementation decreased oxLDL-induced trained immunity in the MetSyn group for LPS-induced IL-6 responses and Pam3CSK4-induced TNF-α responses. Induction of trained immunity by β-glucan was decreased by butyrate in the MetSyn group for Pam3CSK4-induced IL-10 production. In this study, while having only limited effects on the direct stimulation of cytokine production, butyrate supplementation significantly affected trained immunity in monocytes of obese individuals with metabolic complications. Therefore, oral butyrate supplementation may be beneficial in reducing the overall inflammatory status of circulating monocytes in patients with metabolic syndrome.
OBJECTIVE—Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local ...and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).
APPROACH AND RESULTS—Arterial wall inflammation and bone marrow activity were measured using F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol3.26 2.07–5.71) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 0.27–0.40; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytesPatients with FD 92% 86–95, controls 76% 66–81, P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10–276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.
CONCLUSIONS—Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
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