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Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages.

ABSTRACT: Trained immunity is a form of innate immune memory best described in mice and humans. Clear evidence of the evolutionary conservation of trained immunity in teleost fish is lacking. Given the evolutionary position of teleosts as early vertebrates with a fully developed immune system, we hypothesize that teleost myeloid cells show features of trained immunity common to those observed in mammalian macrophages. These would at least include the ability of fish macrophages to mount heightened responses to a secondary stimulus in a nonspecific manner. We established an in vitro model to study trained immunity in fish by adapting a well-described culture system of head kidney-derived macrophages of common carp. A soluble NOD-specific ligand and a soluble β-glucan were used to train carp macrophages, after which cells were rested for 6 d prior to exposure to a secondary stimulus. Unstimulated trained macrophages displayed evidence of metabolic reprogramming as well as heightened phagocytosis and increased expression of the inflammatory cytokines il6 and tnf-α. Stimulated trained macrophages showed heightened production of reactive oxygen and nitrogen species as compared with the corresponding stimulated but untrained cells. We discuss the value of our findings for future studies on trained immunity in teleost fish.

SUBMITTER: Petit J

PROVIDER: S-EPMC6571502 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages.

Petit Jules J Embregts Carmen W E CWE Forlenza Maria M Wiegertjes Geert F GF

Journal of immunology (Baltimore, Md. : 1950) 20190524 1

Trained immunity is a form of innate immune memory best described in mice and humans. Clear evidence of the evolutionary conservation of trained immunity in teleost fish is lacking. Given the evolutionary position of teleosts as early vertebrates with a fully developed immune system, we hypothesize that teleost myeloid cells show features of trained immunity common to those observed in mammalian macrophages. These would at least include the ability of fish macrophages to mount heightened respons ...[more]

PMID: 31127029

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Project description:Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.

Project description:Antimicrobial resistance (AMR) is a significant problem in health care, animal health, and food safety. To limit AMR, there is a need for alternatives to antibiotics to enhance disease resistance and support judicious antibiotic usage in animals and humans. Immunomodulation is a promising strategy to enhance disease resistance without antibiotics in food animals. One rapidly evolving field of immunomodulation is innate memory in which innate immune cells undergo epigenetic changes of chromatin remodeling and metabolic reprogramming upon a priming event that results in either enhanced or suppressed responsiveness to secondary stimuli (training or tolerance, respectively). Exposure to live agents such as bacille Calmette-Guerin (BCG) or microbe-derived products such as LPS or yeast cell wall ß-glucans can reprogram or "train" the innate immune system. Over the last decade, significant advancements increased our understanding of innate training in humans and rodent models, and strategies are being developed to specifically target or regulate innate memory. In veterinary species, the concept of enhancing the innate immune system is not new; however, there are few available studies which have purposefully investigated innate training as it has been defined in human literature. The development of targeted approaches to engage innate training in food animals, with the practical goal of enhancing the capacity to limit disease without the use of antibiotics, is an area which deserves attention. In this review, we provide an overview of innate immunomodulation and memory, and the mechanisms which regulate this long-term functional reprogramming in other animals (e.g., humans, rodents). We focus on studies describing innate training, or similar phenomenon (often referred to as heterologous or non-specific protection), in cattle, sheep, goats, swine, poultry, and fish species; and discuss the potential benefits and shortcomings of engaging innate training for enhancing disease resistance.

Project description:BackgroundCardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics.MethodsBone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) Ldlr-/- mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection.ResultsIn macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) Ldlr-/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype.ConclusionsHyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.

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Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages.

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Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages.

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