scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals Controlled Human Malaria Infection Induces Long-Term Functional Changes in Monocytes

2020 ◽  
Vol 7 ◽  
Author(s):  
Jona Walk ◽  
Farid Keramati ◽  
L. Charlotte J. de Bree ◽  
Rob J. W. Arts ◽  
Bas Blok ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Oxidized Ldl ◽  
Acute Infection ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Human Malaria ◽  
Trained Immunity ◽  
Controlled Human Malaria Infection

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 phenotype remained uncertain. We evaluated whether Plasmodium falciparum infection can induce innate immune memory by measuring monocyte-derived cytokine production from five volunteers undergoing Controlled Human Malaria Infection. Monocyte responses followed a biphasic pattern: during acute infection, monocytes produced lower amounts of inflammatory cytokines upon secondary stimulation, but 36 days after malaria infection they produced significantly more IL-6 and TNF-α in response to various stimuli. Furthermore, transcriptomic and epigenomic data analysis revealed a clear reprogramming of monocytes at both timepoints, with long-term changes of H3K4me3 at the promoter regions of inflammatory genes that remain present for several weeks after parasite clearance. These findings demonstrate an epigenetic basis of trained immunity induced by human malaria in vivo.

scholarly journals Trained immunity: A program of innate immune memory in health and disease

Science ◽  
2016 ◽  
Vol 352 (6284) ◽  
pp. aaf1098-aaf1098 ◽  
Author(s):  
M. G. Netea ◽  
L. A. B. Joosten ◽  
E. Latz ◽  
K. H. G. Mills ◽  
G. Natoli ◽  
...  
Keyword(s):  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity ◽  
Health And Disease

scholarly journals Trained Immunity at a Glance; A Review on the Innate Immune Memory and its Potential Role in Infections, Diseases and New Therapeutic Strategies

2020 ◽  
Vol 8 (1) ◽  
pp. 68-81
Author(s):  
Silvia Incalcaterra ◽  
Jorge Andres Dominguez
Keyword(s):  
Therapeutic Strategies ◽  
Innate Immune ◽  
Immune Memory ◽  
Therapeutic Approaches ◽  
Trained Immunity ◽  
Adaptive Immune ◽  
Specific Memory ◽  
Health And Disease ◽  
The Impact ◽  
Infections Diseases

Despite the existence of two different branches of immunity, innate and adaptive, it has been described that both systems are characterized by the establishment of memory responses. Indeed, it has been shown that cells belonging to the innate immune system can express a so-called “trained” memory, although it has different features from the adaptive immune memory. Adaptive memory is a long-lasting specific memory whereas innate memory involves non-specific responses which enhance the immune response during a second reinfection. However, many aspects of the trained immunity are still unclear. Metabolic and epigenetic reprogramming have been pointed as the two processes responsible for the establishment of the innate memory. Trained immunity seems to be responsible for the heterologous effect of many vaccines such as BCG, thus giving insights for the development of new therapies. Although its potential beneficial role, trained immunity could also have detrimental effects that might worsen the progress of certain diseases. The purpose of this literature review is to provide an in-depth review on the major characteristics of trained immunity, describing the main pathways at the basis of the evolution and establishment of memory in innate cells. In addition, the present review assesses the modern evidence of the impact of trained immunity in health and disease, strengthening the hypotheses that this innate memory may be considered both in the formulation of new therapeutic strategies and in the current therapeutic approaches.

scholarly journals Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

2020 ◽  
Author(s):  
Yiwei Feng ◽  
Tengteng Wu ◽  
Yukun Feng ◽  
Fengyin Liang ◽  
Ge Li ◽  
...  
Keyword(s):  
Detrimental Effect ◽  
Recurrent Stroke ◽  
Ischemic Injury ◽  
The Elderly ◽  
Potential Effect ◽  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity ◽  
Photothrombotic Stroke

AbstractMicroinfarcts are common among the elderly, and patients with microinfarcts are more vulnerable to another stroke. However, the potential effect of microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.

scholarly journals Induction of Trained Innate Immunity in Human Monocytes by Bovine Milk and Milk-Derived Immunoglobulin G

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1378 ◽  
Author(s):  
Marloes van Splunter ◽  
Thijs van Osch ◽  
Sylvia Brugman ◽  
Huub Savelkoul ◽  
Leo Joosten ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immunoglobulin G ◽  
Cytokine Production ◽  
Bovine Milk ◽  
Innate Immune ◽  
Immune Memory ◽  
Bovine Lactoferrin ◽  
Human Monocytes ◽  
Trained Immunity

Innate immune memory, also termed “trained immunity” in vertebrates, has been recently described in a large variety of plants and animals. In most cases, trained innate immunity is induced by pathogens or pathogen-associated molecular patterns (PAMPs), and is associated with long-term epigenetic, metabolic, and functional reprogramming. Interestingly, recent findings indicate that food components can mimic PAMPs effects and induce trained immunity. The aim of this study was to investigate whether bovine milk or its components can induce trained immunity in human monocytes. To this aim, monocytes were exposed for 24 h to β-glucan, Toll-like receptor (TLR)-ligands, bovine milk, milk fractions, bovine lactoferrin (bLF), and bovine Immunoglobulin G (bIgG). After washing away the stimulus and a resting period of five days, the cells were re-stimulated with TLR ligands and Tumor necrosis factor (TNF-) and interleukin (IL)-6 production was measured. Training with β-glucan resulted in higher cytokine production after TLR1/2, TLR4, and TLR7/8 stimulation. When monocytes trained with raw milk were re-stimulated with TLR1/2 ligand Pam3CSK4, trained cells produced more IL-6 compared to non-trained cells. Training with bIgG resulted in higher cytokine production after TLR4 and TLR7/8 stimulation. These results show that bovine milk and bIgG can induce trained immunity in human monocytes. This confirms the hypothesis that diet components can influence the long-term responsiveness of the innate immune system.

scholarly journals The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

2021 ◽  
Vol 22 (5) ◽  
pp. 2578
Author(s):  
Trim Lajqi ◽  
Christian Marx ◽  
Hannes Hudalla ◽  
Fabienne Haas ◽  
Silke Große ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Low Dose ◽  
Innate Immune ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Atp Production ◽  
Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

scholarly journals Trained Immunity and Local Innate Immune Memory in the Lung

Cell ◽  
2018 ◽  
Vol 175 (6) ◽  
pp. 1463-1465 ◽  
Author(s):  
Mihai G. Netea ◽  
Leo A.B. Joosten
Keyword(s):  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity

scholarly journals Dysbiosis From a Microbial and Host Perspective Relative to Oral Health and Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Carla Cugini ◽  
Narayanan Ramasubbu ◽  
Vincent K. Tsiagbe ◽  
Daniel H. Fine
Keyword(s):  
Oral Disease ◽  
Oral Diseases ◽  
Oral Infections ◽  
The Future ◽  
Technical Advances ◽  
Health And Disease ◽  
Oral Microbiology ◽  
Immunological Research

The significance of microbiology and immunology with regard to caries and periodontal disease gained substantial clinical or research consideration in the mid 1960's. This enhanced emphasis related to several simple but elegant experiments illustrating the relevance of bacteria to oral infections. Since that point, the understanding of oral diseases has become increasingly sophisticated and many of the original hypotheses related to disease causality have either been abandoned or amplified. The COVID pandemic has reminded us of the importance of history relative to infectious diseases and in the words of Churchill “those who fail to learn from history are condemned to repeat it.” This review is designed to present an overview of broad general directions of research over the last 60 years in oral microbiology and immunology, reviewing significant contributions, indicating emerging foci of interest, and proposing future directions based on technical advances and new understandings. Our goal is to review this rich history (standard microbiology and immunology) and point to potential directions in the future (omics) that can lead to a better understanding of disease. Over the years, research scientists have moved from a position of downplaying the role of bacteria in oral disease to one implicating bacteria as true pathogens that cause disease. More recently it has been proposed that bacteria form the ecological first line of defense against “foreign” invaders and also serve to train the immune system as an acquired host defensive stimulus. While early immunological research was focused on immunological exposure as a modulator of disease, the “hygiene hypothesis,” and now the “old friends hypothesis” suggest that the immune response could be trained by bacteria for long-term health. Advanced “omics” technologies are currently being used to address changes that occur in the host and the microbiome in oral disease. The “omics” methodologies have shaped the detection of quantifiable biomarkers to define human physiology and pathologies. In summary, this review will emphasize the role that commensals and pathobionts play in their interaction with the immune status of the host, with a prediction that current “omic” technologies will allow researchers to better understand disease in the future.

scholarly journals The Potential Effects of Short-Chain Fatty Acids on the Epigenetic Regulation of Innate Immune Memory

Challenges ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 25
Author(s):  
Raphael Watt ◽  
Kimberley Parkin ◽  
David Martino
Keyword(s):  
Fatty Acids ◽  
Innate Immunity ◽  
Epigenetic Regulation ◽  
Early Life ◽  
Short Chain Fatty Acids ◽  
Innate Immune ◽  
Short Chain ◽  
Immune Memory ◽  
Trained Immunity ◽  
Chain Fatty Acids

The regulation of innate immunity is substantially more ‘plastic’ than previously appreciated. Innate immune memory (manifested through trained immunity and tolerance) is a recently described epigenetic phenomenon that is a model example, with broad implications for infectious disease, allergy and autoimmunity. Training the innate immune system to combat infections and temper inappropriate responses in non-communicable diseases will likely be an area of intense research. Innate immunity is influenced by short chain fatty acids, which are the natural products of digestion by the intestinal microbiota that possess inherent histone deacetylase inhibitory properties. It therefore stands to reason that a healthy gut microbiome may well influence mucosal and systemic trained immunity via short chain fatty acids. There is a lack of data on this specific topic, and we discuss potential relationships based on available and preliminary evidence. Understanding the link between intestinal microbiome composition, capacity for short chain fatty acid production and downstream effects on innate immune memory in early life will have important implications for host immunobiology. In this review we explore the intersection between the gut microbiota, short chain fatty acids and epigenetic regulation of innate immunity with a focus on early life.

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