Trained Immunity and Local Innate Immune Memory in the Lung

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.

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

Challenges ◽

10.3390/challe11020025 ◽

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

Science ◽

10.1126/science.aaf1098 ◽

2016 ◽

Vol 352 (6284) ◽

pp. aaf1098-aaf1098 ◽

Cited By ~ 869

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

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A Prime Time for Trained Immunity: Innate Immune Memory in Newborns and Infants

Neonatology ◽

10.1159/000356035 ◽

2013 ◽

Vol 105 (2) ◽

pp. 136-141 ◽

Cited By ~ 49

Author(s):

Ofer Levy ◽

James L. Wynn

Keyword(s):

Innate Immune ◽

Immune Memory ◽

Prime Time ◽

Trained Immunity

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

Advanced Journal of Graduate Research ◽

10.21467/ajgr.8.1.68-81 ◽

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.

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Exposome and Immunity Training: How Pathogen Exposure Order Influences Innate Immune Cell Lineage Commitment and Function

International Journal of Molecular Sciences ◽

10.3390/ijms21228462 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8462

Author(s):

Kevin Adams ◽

K. Scott Weber ◽

Steven M. Johnson

Keyword(s):

Immune Cell ◽

Cell Lineage ◽

Innate Immune ◽

Lineage Commitment ◽

Immune Memory ◽

Key Factors ◽

Hematopoietic Stem ◽

Trained Immunity ◽

Stem Cell Lineage ◽

And Function

Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined “trained immunity” and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The “exposome” is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality.

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

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.604553 ◽

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.

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Trained Immunity

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314212 ◽

2020 ◽

Author(s):

Helin Tercan ◽

Niels P. Riksen ◽

Leo A.B. Joosten ◽

Mihai G. Netea ◽

Siroon Bekkering

Keyword(s):

Immune Cells ◽

Inflammatory Diseases ◽

Oxidized Ldl ◽

Density Lipoprotein ◽

Innate Immune ◽

Immune Memory ◽

Innate Immune Cells ◽

Antigen Specificity ◽

Trained Immunity

Adaptive immune responses are characterized by antigen specificity and induction of lifelong immunologic memory. Recently, it has been reported that innate immune cells can also build immune memory characteristics—a process termed trained immunity. Trained immunity describes the persistent hyperresponsive phenotype that innate immune cells can develop after brief stimulation. Pathogenic stimuli such as microorganisms, and also endogenous molecules including uric acid, oxidized LDL (low-density lipoprotein), and catecholamines, are capable of inducing memory in monocytes and macrophages. While trained immunity provides favorable cross-protection in the context of infectious diseases, the heightened immune response can be maladaptive in diseases driven by chronic systemic inflammation, such as atherosclerosis. Trained immunity is maintained by distinct epigenetic and metabolic mechanisms and persists for at least several months in vivo due to reprogramming of myeloid progenitor cells. Additionally, certain nonimmune cells are also found to exhibit trained immunity characteristics. Thus, trained immunity presents an exciting framework to develop new approaches to vaccination and also novel pharmacological targets in the treatment of inflammatory diseases.

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

10.1101/2020.06.17.157289 ◽

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.

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

Nutrients ◽

10.3390/nu10101378 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1378 ◽

Cited By ~ 9

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.

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