Rob Arts

Rob Arts
Radboud University Medical Centre (Radboudumc) · Department of Internal Medicine

MD, PhD

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86
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Publications (86)
Article
Trained immunity is the long-term memory of innate immune cells, characterised by increased pro-inflammatory responses towards homo- and heterologous secondary stimuli. Interleukin (IL)-1 signalling plays an essential role in the induction of trained immunity, also called innate immune memory. As such, certain anti-inflammatory members of the IL-1...
Article
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Introduction Patients with clinical malaria have an increased risk for bacterial bloodstream infections. We hypothesized that asymptomatic malaria parasitemia increases susceptibility for bacterial infections through an effect on the innate immune system. We measured circulating cytokine levels and ex-vivo cytokine production capacity in asymptomat...
Article
Trained immunity (TI) is a pro-inflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and characterized by immunometabolic and epigenetic changes enhancing cytokine production. Maladaptive activation of TI (i.e., in the absence of infection) might result in detrimental inflammation and disease development; however,...
Article
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Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activ...
Article
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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 blo...
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Objectives Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trai...
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Trained immunity is the acquisition of a hyperresponsive phenotype by innate immune cells (such as monocytes and macrophages) after an infection or vaccination, a de facto nonspecific memory dependent on epigenetic and metabolic reprogramming of these cells. We have recently shown that induction of trained immunity is dependent on IL‐1β. Here, we s...
Article
Full-text available
Innate immune memory responses (also termed “ trained immunity ”) have been described in monocytes after BCG vaccination and after stimulation in vitro with microbial and endogenous ligands such as LPS, β-glucan, oxidized LDL, and monosodium urate crystals. However, whether clinical infections are also capable of inducing a trained immunity phenoty...
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BACKGROUND The antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG...
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Background: Induction of innate immune memory, also termed trained immunity, by the anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known: while induction of trained immunity may sugg...
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The Vi polysaccharide typhoid fever vaccine (TFV) provides incomplete protection against typhoid fever. BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investi...
Article
Background Histiocytoses are disorders characterized by tissue infiltration by macrophages, dendritic cells, or monocyte-derived cells. These diseases are classified in five groups based on histologic, clinical, and molecular features: Langerhans-related, cutaneous/mucocutaneous and malignant histiocytoses, Rosai-Dorfman disease, and hemophagocytic...
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The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase pr...
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Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to an...
Conference Paper
Background Trained immunity (TI) is a de-facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as a protective mechanism against infections. TI is characterized by rewiring of functional, epigenetic and metabolic programs of innate immune cells such as monocytes and macrophages, whic...
Article
Background: Some strains of Bacillus Calmette-Guérin (BCG) vaccine not only confer protection against disseminated forms of tuberculosis, but also reduce all-cause mortality by the induction of protection against infections with non-related pathogens. Objectives: We review evidence for non-specific protection induced by BCG vaccination against v...
Conference Paper
Career situation of first and presenting author Assistant. Introduction Trained immunity (TI) is a de-facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as a protective mechanism against infections. TI is characterized by rewiring of functional, epigenetic and metabolic programs...
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Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the inductio...
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Background: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. Methods: We investigated in vitro and in vivo effects of metformin in humans. Results: Metformin adde...
Article
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conduc...
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Endoreplication is a cell cycle program in which cells replicate their genomes without undergoing mitosis and cytokinesis. For the normal development of many organisms (from fungi to humans) and the formation of their organs, endoreplication is indispensable. The aim of the present study was to explore whether endoreplication and DNA synthesis are...
Article
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 immun...
Article
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 gat...
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High-mobility group nucleosome-binding protein 1 (HMGN1) functions as a non-histone chromatin-binding protein in the cell nucleus. However, extracellular HMGN1 acts as an endogenous danger-associated inflammatory mediator (also called alarmin). We demonstrated that HMGN1 not only directly stimulated cytokine production but also had the capacity to...
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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 glutamin...
Article
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. We used a PBMC-based "mycobacterial-growth-inhibition-assay" (MGIA) to investigate the capacity t...
Article
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...
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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 agai...
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Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimul...
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Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyph...
Data
Transcriptome analysis after stimulation of PBMCs with C. albicans. (A and B) Pathway map of the gene expression in the main metabolic pathways in PBMCs stimulated with heat-killed C. albicans yeast 4 h (A) and 24 h (B) after the stimulation. The transcripts marked in red were significantly upregulated in C. albicans versus RPMI. (TIF)
Data
Glycolysis, glutaminolysis and oxidative phosphorylation differentially affected Th1/Th17-derived cytokine production in PBMCs. (A-B) IL-17, IL-22 and IFNγ production by human PBMCs treated with different metabolic inhibitors and stimulated with heat-killed C. albicans yeast (A) or heat-killed C. albicans hyphae (B) for 7 days. IL-10 production was...
Data
Viability of human PBMCs treated with metabolic inhibitors. PBMCs were stained for Annexin V and propidium iodide. Annexin V+ cells were considered as early apoptotic cells and Annexin V+ / PI+ cells were considered as late apoptotic cells. (mean ± SEM, n = 3). Similar results were obtained in 3 independent experiments. (TIF)
Data
OCR/ECAR ratios. Basal and maximum OCR/ECAR ratios obtained after 4 h and 24 h stimulation of monocytes with medium or heat-killed C. albicans yeast (mean ± SEM, n = 6–8; pooled from 2 independent experiments). (TIF)
Data
C-type lectins triggered glycolysis after stimulation with Candida yeast. (A-B) Lactate production by human monocytes was measured after adding the corresponding isotype controls of the blockers used in Fig 4 and the subsequent 24 h-stimulation with medium, heat-killed C. albicans yeast or heat-killed C. albicans hyphae (A) or hgc1 or Δhgc1 live C....
Data
ROS production by monocytes involved glycolysis and the pentose phosphate pathway. (A-D) Human monocytes were treated with DMSO (A), Torin1 (B), AICAR (C) or BPTES (D) and subsequently stimulated with medium, heat-killed C. albicans yeast or heat-killed C. albicans hyphae. Luminescence generated from ROS production was measured every 145 seconds du...
Data
Phagocytic capacity of monocytes after 2-DG treatment. (mean ± SEM, n = 12; pooled from 4 independent experiments). (TIF)
Data
Direct effects of 2-DG on mouse neutrophils. (A-B) Candidacidal activity of neutrophils isolated from blood of non-infected C57BL/6 mice following the protocol described in (A) after in vitro treatment of cells with PBS or 11 mM 2-DG (mean ± SEM, n = 6). *p< 0.05, Student’s t test. Each dot represents one mouse. (TIF)
Data
Primers for real-time PCR. (DOCX)
Article
Full-text available
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 i...
Article
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...
Article
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. Me...
Article
The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comp...
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Full-text available
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...
Article
Full-text available
Tumor associated macrophages (TAMs) are key components of the tumor microenvironment in non-medullary thyroid cancer (TC), the most common endocrine malignancy. However, little is known regarding the regulation of their function in TC. Transcriptome analysis in a model of TC-induced macrophages identified increased inflammatory characteristics and...
Article
Adaptive Characteristics of Innate Immune Responses in Macrophages, Page 1 of 2 Abstract The innate immune system is considered to have no immune memory. However, lately there has been as shift in paradigm. Cells of the innate immune system, and especially monocytes and macrophages, are capable of building a nonspecific memory, resulting in eithe...
Article
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, t...
Article
Background: Tumor-associated macrophages (TAMs) with dysregulated inflammatory phenotypes play a key role in carcinogenesis. In thyroid carcinoma (TC), excessive release of proinflammatory cytokines decreases the expression of sodium-iodine transporter and inflammation potentiates tumor progression. Aim: To assess the impact of TC cells on the func...
Article
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 impor...
Article
An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccinat...