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Papers by Rob Arts
International Journal of Molecular Sciences
Trained immunity is the process of long-term functional reprogramming (a de facto innate immune m... more Trained immunity is the process of long-term functional reprogramming (a de facto innate immune memory) of innate immune cells such as monocytes and macrophages after an exposure to pathogens, vaccines, or their ligands. The induction of trained immunity is mediated through epigenetic and metabolic mechanisms. Apart from exogenous stimuli, trained immunity can be induced by endogenous compounds such as oxidized LDL, urate, fumarate, but also cytokines including IL-1α and IL-1β. Here, we show that also recombinant IL-36γ, a pro-inflammatory cytokine of the IL-1-family, is able to induce trained immunity in primary human monocytes, demonstrated by higher cytokine responses and an increase in cellular metabolic pathways both regulated by epigenetic histone modifications. These effects could be inhibited by the IL-36 receptor antagonist as well as by IL-38, an anti-inflammatory cytokine of the IL-1 family which shares its main receptor with IL-36 (IL-1R6). Further, we demonstrated that ...
Frontiers in Immunology
Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-i... more Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-inflammatory properties similar to IL-36Ra. Several studies compared circulating IL-38 concentrations in healthy and diseased populations to characterize its role in both auto-immune and inflammatory pathologies, with both higher and lower concentrations being associated with certain diseases. However, in order to use IL-38 as a biomarker, a reference range in healthy adults is needed. To establish a reference IL-38 circulating concentration, accessible data from 25 eligible studies with IL-38 concentrations in healthy adults was collected. To validate the values found in literature, we measured IL-38 concentrations by enzyme-linked immunosorbent assay (ELISA) in several cohorts from our own institute. Additionally, the effect of blood collection techniques, freeze thawing cycles, and hemolysis on IL-38 measurements was assessed. To evaluate the importance of the genetic background of ind...
STAR Protocols, 2021
In vitro induction of trained immunity in adherent human monocytes A growing number of studies sh... more In vitro induction of trained immunity in adherent human monocytes A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed ''trained immunity.'' We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using b-glucan (from Candida albicans) and Bacillus Calmette-Gué rin as examples.
JCI insight, Jan 9, 2018
Limited understanding of the mechanisms responsible for life-threatening organ and immune failure... more Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists' ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.
Immunity, 2018
Highlights d Vimentin and HMGB1 promote training of graft-infiltrating macrophages d HDL-nanobiol... more Highlights d Vimentin and HMGB1 promote training of graft-infiltrating macrophages d HDL-nanobiologics target myeloid cells in hematopoietic organs and the allograft d mTORi-HDL prevents trained immunity and TRAF6i-HDL inhibits CD40 costimulation d Nanoimmunotherapy with both mTORi-and TRAF6i-HDL induces organ transplant acceptance
Cell metabolism, 2018
Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading t... more Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. β-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune toleranc...
Frontiers in immunology, 2018
During induction of trained immunity, monocytes and macrophages undergo a functional and transcri... more During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
The Journal of clinical investigation, Jan 3, 2018
The lack of defined correlates of protection hampers development of vaccines against tuberculosis... more The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-e...
Cell host & microbe, Jan 10, 2018
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects again... more The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-rela...
Cell, Jan 11, 2018
Innate immune cells can develop long-term memory after stimulation by microbial products during i... more 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...
The Journal of allergy and clinical immunology, Jan 4, 2017
Cell, 2016
The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalogue of ... more The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalogue of high-resolution reference epigenomes of major primary human cell types. The studies now presented (cell.com/XXXXXXX) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic data sets to gain insights in the epigenetic control of cell states relevant for human health and disease.
Seminars in immunology, Oct 1, 2016
The classical view that only adaptive immunity can build immunological memory has recently been c... more The classical view that only adaptive immunity can build immunological memory has recently been challenged. Both in organisms lacking adaptive immunity as well as in mammals, the innate immune system can adapt to mount an increased resistance to reinfection, a de facto innate immune memory termed trained immunity. Recent studies have revealed that rewiring of cellular metabolism induced by different immunological signals is a crucial step for determining the epigenetic changes underlying trained immunity. Processes such as a shift of glucose metabolism from oxidative phosphorylation to aerobic glycolysis, increased glutamine metabolism and cholesterol synthesis, play a crucial role in these processes. The discovery of trained immunity opens the door for the design of novel generations of vaccines, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases.
Cell reports, Dec 6, 2016
The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated in... more The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may...
Cell metabolism, Dec 13, 2016
Induction of trained immunity (innate immune memory) is mediated by activation of immune and meta... more 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 ...
Cell, 2016
Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophag... more Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, β-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo β-glucan treatment of monocytes from volunteers with experimental endotoxemia reinstates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes.
Journal of leukocyte biology, Jan 6, 2016
In recent years, it has become appreciated that immune cells have different metabolic profiles de... more In recent years, it has become appreciated that immune cells have different metabolic profiles depending on their activation status. During sepsis, circulating leukocytes go through a hyperinflammatory state, which can be accompanied or followed by defective antimicrobial defenses (also described as immune tolerance or paralysis). In this review, the modulation of different cellular metabolic pathways during sepsis in monocytes and macrophages will be discussed. Glycolysis is studied extensively in sepsis and is up-regulated in hyperinflammatory cells, whereas in immune tolerance, it is often down-regulated. Few data are available on other metabolic pathways in immune cells from patients with sepsis. The pentose phosphate pathway is up-regulated during acute hyperinflammatory responses, whereas fatty acid β-oxidation is increased later during sepsis and is associated with an anti-inflammatory (M2) phenotype of macrophages. Within the amino acid metabolism we will discuss the most st...
Endocrine Abstracts, 2016
The Turkish Journal of Gastroenterology, 2012
Nature immunology, Jan 7, 2016
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in ... more The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might...
International Journal of Molecular Sciences
Trained immunity is the process of long-term functional reprogramming (a de facto innate immune m... more Trained immunity is the process of long-term functional reprogramming (a de facto innate immune memory) of innate immune cells such as monocytes and macrophages after an exposure to pathogens, vaccines, or their ligands. The induction of trained immunity is mediated through epigenetic and metabolic mechanisms. Apart from exogenous stimuli, trained immunity can be induced by endogenous compounds such as oxidized LDL, urate, fumarate, but also cytokines including IL-1α and IL-1β. Here, we show that also recombinant IL-36γ, a pro-inflammatory cytokine of the IL-1-family, is able to induce trained immunity in primary human monocytes, demonstrated by higher cytokine responses and an increase in cellular metabolic pathways both regulated by epigenetic histone modifications. These effects could be inhibited by the IL-36 receptor antagonist as well as by IL-38, an anti-inflammatory cytokine of the IL-1 family which shares its main receptor with IL-36 (IL-1R6). Further, we demonstrated that ...
Frontiers in Immunology
Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-i... more Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-inflammatory properties similar to IL-36Ra. Several studies compared circulating IL-38 concentrations in healthy and diseased populations to characterize its role in both auto-immune and inflammatory pathologies, with both higher and lower concentrations being associated with certain diseases. However, in order to use IL-38 as a biomarker, a reference range in healthy adults is needed. To establish a reference IL-38 circulating concentration, accessible data from 25 eligible studies with IL-38 concentrations in healthy adults was collected. To validate the values found in literature, we measured IL-38 concentrations by enzyme-linked immunosorbent assay (ELISA) in several cohorts from our own institute. Additionally, the effect of blood collection techniques, freeze thawing cycles, and hemolysis on IL-38 measurements was assessed. To evaluate the importance of the genetic background of ind...
STAR Protocols, 2021
In vitro induction of trained immunity in adherent human monocytes A growing number of studies sh... more In vitro induction of trained immunity in adherent human monocytes A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed ''trained immunity.'' We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using b-glucan (from Candida albicans) and Bacillus Calmette-Gué rin as examples.
JCI insight, Jan 9, 2018
Limited understanding of the mechanisms responsible for life-threatening organ and immune failure... more Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists' ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.
Immunity, 2018
Highlights d Vimentin and HMGB1 promote training of graft-infiltrating macrophages d HDL-nanobiol... more Highlights d Vimentin and HMGB1 promote training of graft-infiltrating macrophages d HDL-nanobiologics target myeloid cells in hematopoietic organs and the allograft d mTORi-HDL prevents trained immunity and TRAF6i-HDL inhibits CD40 costimulation d Nanoimmunotherapy with both mTORi-and TRAF6i-HDL induces organ transplant acceptance
Cell metabolism, 2018
Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading t... more Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. β-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune toleranc...
Frontiers in immunology, 2018
During induction of trained immunity, monocytes and macrophages undergo a functional and transcri... more During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
The Journal of clinical investigation, Jan 3, 2018
The lack of defined correlates of protection hampers development of vaccines against tuberculosis... more The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-e...
Cell host & microbe, Jan 10, 2018
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects again... more The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-rela...
Cell, Jan 11, 2018
Innate immune cells can develop long-term memory after stimulation by microbial products during i... more 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...
The Journal of allergy and clinical immunology, Jan 4, 2017
Cell, 2016
The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalogue of ... more The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalogue of high-resolution reference epigenomes of major primary human cell types. The studies now presented (cell.com/XXXXXXX) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic data sets to gain insights in the epigenetic control of cell states relevant for human health and disease.
Seminars in immunology, Oct 1, 2016
The classical view that only adaptive immunity can build immunological memory has recently been c... more The classical view that only adaptive immunity can build immunological memory has recently been challenged. Both in organisms lacking adaptive immunity as well as in mammals, the innate immune system can adapt to mount an increased resistance to reinfection, a de facto innate immune memory termed trained immunity. Recent studies have revealed that rewiring of cellular metabolism induced by different immunological signals is a crucial step for determining the epigenetic changes underlying trained immunity. Processes such as a shift of glucose metabolism from oxidative phosphorylation to aerobic glycolysis, increased glutamine metabolism and cholesterol synthesis, play a crucial role in these processes. The discovery of trained immunity opens the door for the design of novel generations of vaccines, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases.
Cell reports, Dec 6, 2016
The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated in... more The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may...
Cell metabolism, Dec 13, 2016
Induction of trained immunity (innate immune memory) is mediated by activation of immune and meta... more 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 ...
Cell, 2016
Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophag... more Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, β-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo β-glucan treatment of monocytes from volunteers with experimental endotoxemia reinstates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes.
Journal of leukocyte biology, Jan 6, 2016
In recent years, it has become appreciated that immune cells have different metabolic profiles de... more In recent years, it has become appreciated that immune cells have different metabolic profiles depending on their activation status. During sepsis, circulating leukocytes go through a hyperinflammatory state, which can be accompanied or followed by defective antimicrobial defenses (also described as immune tolerance or paralysis). In this review, the modulation of different cellular metabolic pathways during sepsis in monocytes and macrophages will be discussed. Glycolysis is studied extensively in sepsis and is up-regulated in hyperinflammatory cells, whereas in immune tolerance, it is often down-regulated. Few data are available on other metabolic pathways in immune cells from patients with sepsis. The pentose phosphate pathway is up-regulated during acute hyperinflammatory responses, whereas fatty acid β-oxidation is increased later during sepsis and is associated with an anti-inflammatory (M2) phenotype of macrophages. Within the amino acid metabolism we will discuss the most st...
Endocrine Abstracts, 2016
The Turkish Journal of Gastroenterology, 2012
Nature immunology, Jan 7, 2016
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in ... more The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might...