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 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 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.

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 Adipose tissue induces trained innate immunity in patients with obesity

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Van Tuijl ◽  
D Vreeken ◽  
W Broeders ◽  
R Stienstra ◽  
L A B Joosten ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune System ◽  
Innate Immune System ◽  
Cytokine Production ◽  
Production Capacity ◽  
Innate Immune ◽  
Healthy Human ◽  
Trained Immunity

Abstract Introduction Obesity is the most prevalent modifiable risk factor for atherosclerotic cardiovascular disease and is characterized as a chronic inflammatory disease. Cells of the innate immune system, especially monocytes and macrophages, play a pivotal role in the various stages of atherosclerosis, although it still remains elusive why the strong inflammatory response persists in time. We recently showed that cells of the innate immune system, such as monocytes, can adopt a long-term immunological memory. Upon brief stimulation with atherogenic stimuli, monocytes demonstrate an enhanced long-term pro-inflammatory and pro-atherogenic phenotype. This is termed trained immunity and is mediated via epigenetic and metabolic reprogramming. The clinical relevance of these findings was verified in patients with symptomatic atherosclerosis, in which circulating monocytes showed a trained immune phenotype. Purpose As various adipose tissue-related particles, including pro-inflammatory cytokines and fatty acids, are capable of inducing trained immunity in vitro, we hypothesized that adipose tissue from obese subjects might induce training in peripheral monocytes, thereby contributing to the increased risk of atherosclerotic CVD in these patients. In line with this hypothesis, it is unclear whether chronic inflammation sustains after a previous period of obesity despite significant weight loss. Methods We obtained blood from 25 patients with obesity before and 6 months after bariatric surgery. Monocyte subsets and activation phenotype were studied using flow cytometry. Cytokine production capacity of isolated PBMCs was studied after ex vivo stimulation with several infectious and metabolic stimuli and we characterized isolated monocytes using transcriptomics. Next, we obtained visceral (VAT) and subcutaneous adipose tissue (SAT) biopsies from 10 patients. Using our established in vitro model for trained immunity, we co-incubated healthy human monocytes with the adipose tissue biopsies for 24 hours in a trans-well set-up. After 24 hours, the adipose tissue was removed and monocytes were rested. On day 6, the cells were re-stimulated for 24 hours with a second stimulus and cytokine production and the transcriptome of the macrophages was analyzed. Results Both SAT and VAT obtained from patients with obesity can induce a long-term memory in healthy human monocytes, as demonstrated by an increased cytokine production capacity 6 days after co-incubation. Interestingly, VAT induced a higher cytokine response compared to SAT. Analysis of the inflammatory phenotype of peripheral cells before and after bariatric surgery is currently ongoing. Conclusions Adipose tissue-secreted metabolites, particularly secreted by VAT, have the potential to induce persistent innate immune cell activation. Our further analyses will show whether the secretion of these molecules and the activation of the innate immune system persists upon weight loss. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation

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 Human Cytomegalovirus UL138 Protein Inhibits the STING Pathway and Reduces Interferon Beta mRNA Accumulation during Lytic and Latent Infections

mBio ◽  
2021 ◽  
Author(s):  
Emily R. Albright ◽  
Clayton K. Mickelson ◽  
Robert F. Kalejta
Keyword(s):  
Innate Immunity ◽  
Interferon Beta ◽  
Viral Latency ◽  
Arms Race ◽  
Innate Immune ◽  
Mrna Accumulation ◽  
Immune Pathway ◽  
Sting Pathway ◽  
Innate Immune Pathway

While a cellular restriction versus viral countermeasure arms race between innate immunity and viral latency is expected, few examples have been documented. Our identification of the first HCMV latency protein that inactivates the cGAS/STING/TBK1 innate immune pathway opens the door to understanding how innate immunity, or its neutralization, impacts long-term persistence by HCMV and other latent viruses.

Innate immune memory of tissue‐resident macrophages and trained innate immunity: Re‐vamping vaccine concept and strategies

2020 ◽  
Vol 108 (3) ◽  
pp. 825-834 ◽  
Author(s):  
Zhou Xing ◽  
Sam Afkhami ◽  
Jegarubee Bavananthasivam ◽  
Dominik K. Fritz ◽  
Michael R. D'Agostino ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Innate Immune ◽  
Immune Memory

scholarly journals DNA Synthesis Is Activated in Mosquitoes and Human Monocytes During the Induction of Innate Immune Memory

2018 ◽  
Vol 9 ◽  
Author(s):  
Jorge Cime-Castillo ◽  
Rob J. W. Arts ◽  
Valeria Vargas-Ponce de León ◽  
Ramon Moreno-Torres ◽  
Salvador Hernández-Martínez ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Innate Immune ◽  
Immune Memory ◽  
Human Monocytes

scholarly journals Cell Therapy With Mesenchymal Stem Cells Induces an Innate Immune Memory Response That Attenuates Experimental Colitis in the Long Term

2020 ◽  
Vol 14 (10) ◽  
pp. 1424-1435 ◽  
Author(s):  
Mercedes Lopez-Santalla ◽  
Rosario Hervas-Salcedo ◽  
Maria Fernandez-Garcia ◽  
Juan Antonio Bueren ◽  
Marina Inmaculada Garin
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Activity Index ◽  
Latency Period ◽  
Innate Immune ◽  
Immune Memory ◽  
Induction Phase ◽  
Rag 1

Abstract Background and Aims Mesenchymal stem cells [MSCs] are used in preclinical and clinical studies for treatment of immune-mediated disorders, thanks to their immunomodulatory properties. Cell therapy with MSCs induces multiple effects in the immune system which ultimately lead to increase in the number of immune cells with regulatory phenotype. In this study, we investigated whether the beneficial effects of MSC therapy are maintained in the long term in a clinically relevant mouse model of colitis. Methods A single dose of adipose-derived MSCs [aMSCs] was infused into dextran sulphate sodium [DSS]-induced colitic mice during the induction phase of the disease. Following a latency period of 12 weeks, mice were re-challenged with a second 7-day cycle of DSS. Results DSS-induced colitic mice treated with aMSCs showed significant reduction in their colitic disease activity index during the second DSS challenge when compared with non-aMSC treated DSS-induced colitic mice. Strikingly, the long-term protection induced by aMSC therapy was also observed in Rag-1-/- mice where no adaptive immune memory cell responses take place. Increased percentages of Ly6G+CD11b+ myeloid cells were observed 12 weeks after the first inflammatory challenge in the peritoneal cavity, spleen, and bone marrow of DSS-induced colitic mice that were infused with aMSCs. Interestingly, upon re-challenge with DSS, these animals showed a concomitant increase in the regulatory/inflammatory macrophage ratio in the colon lamina propria. Conclusions Our findings demonstrate for the first time that MSC therapy can imprint an innate immune memory-like response in mice which confers sustained protection against acute inflammation in the long term.

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