Innate immune cells can adopt long-term inflammatory phenotypes following brief encounters with exogenous (microbial) or endogenous stimuli. This phenomenon is named trained immunity and can improve ...host defense against (recurrent) infections. In contrast, trained immunity can also be maladaptive in the context of chronic inflammatory disorders, such as atherosclerosis. Key to future therapeutic exploitation of this mechanism is thorough knowledge of the mechanisms driving trained immunity, which can be used as pharmacological targets. These mechanisms include profound changes in intracellular metabolism, which are closely intertwined with epigenetic reprogramming at the level of histone modifications. Glycolysis, glutamine replenishment of the tricarboxylic acid cycle with accumulation of fumarate, and the mevalonate pathway have all been identified as critical pathways for trained immunity in monocytes and macrophages. In this review, we provide a state-of-the-art overview of how these metabolic pathways interact with epigenetic programs to develop trained immunity.
The two major challenges in cardiovascular medicine are to refine risk prediction and to improve pharmacological prevention and treatment. The concept of innate immune memory, which is called trained ...immunity, has the potential to improve clinical practice in these regards.
Monocytes and macrophages have the capability to develop a long-term proinflammatory and proatherogenic phenotype after brief exposure to inflammatory stimuli, such as oxidized low-density lipoprotein particles. This innate immune memory develops because of rewiring of intracellular metabolic pathways and epigenetic reprogramming of histone modifications. The persistence of circulating hyperresponsive monocytes in vivo is explained by the fact that training occurs in myeloid progenitor cells in the bone marrow. Several recent studies reported the presence of monocytes with a trained immune phenotype in patients with established atherosclerosis, and in patients with an increased risk for atherosclerosis because of dyslipoproteinemia.
In monocytes and their bone marrow progenitors, metabolic and epigenetic reprogramming can induce trained immunity, which might contribute to the persistent nonresolving inflammation that characterizes atherosclerosis. These pathways offer exciting novel drug targets to improve the prevention and treatment of cardiovascular 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.
Renewed interest in immune cell metabolism has led to the emergence of a research field aimed at studying the importance of metabolic processes for an effective immune response. In addition to the ...adaptive immune system, cells of the myeloid lineage have been shown to undergo robust metabolic changes upon activation. Whereas the specific metabolic requirements of myeloid cells after lipopolysaccharide/TLR4 stimulation have been extensively studied, recent evidence suggested that this model does not represent a metabolic blueprint for activated myeloid cells. Instead, different microbial stimuli, pathogens, or tissue microenvironments lead to specific and complex metabolic rewiring of myeloid cells. Here we present an overview of the metabolic heterogeneity in activated myeloid cells during health and disease. Directions for future research are suggested to ultimately provide new therapeutic opportunities. The uniqueness of metabolic signatures accompanying different conditions will require tailor-made interventions to ultimately modulate aberrant myeloid cell activation during disease.
The importance of intracellular metabolism in determining myeloid cell function has rapidly gained interest. In this review, Stienstra et al. discuss the current state of knowledge in the field of immunometabolism, revealing specific and complex metabolic rewiring in activated myeloid cells in health and disease.
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.
Among infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat, especially in developing countries. The protective effects of Bacillus ...Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to generate trained immunity through the induction of glycolysis and glutaminolysis and the accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge with non-related bacterial stimuli. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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).
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.
Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis ...in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The “red complex” and “cluster B” abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.
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