Elena Berenice Martínez-Shio, Ángel Martín Cárdenas-Hernández, Verónica Jiménez-Suárez, Laura Sherell Marín-Jáuregui, Claudia Castillo-Martin del Campo, Roberto González-Amaro, Carlos D Escobedo-Uribe

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IntroductionDyslipidemia is one of the main modifiable risk factors for the development of cardiovascular diseases (CVD), being the ischemic heart disease the leading cause of mortality in the world. Every year, more people die from CVD than from any other reason, according to data from the World Health Organization, it is estimated that 17.9 million people died from this cause in 2019, which represents 32% of all registered deaths in the world . In addition to high blood pressure, diabetes, obesity, and smoking, dyslipidemia is one of the main cardiovascular risk factors. The latter it is defined as disorders in blood lipids characterized by an increase in cholesterol and/or triglyceride levels called hypercholesterolemia and triglyceridemia, respectively .While most of the triglyceride and cholesterol content is obtained from dietary sources, de novo lipogenesis contributes significantly to serum lipid content in people who have a high-carbohydrate diet. The metabolic pathways by which the macromolecules obtained through the diet are processed, such as glycolysis, Krebs cycle, oxidative phosphorylation, beta oxidation, among others, have as their main function the generation of energy, and an imbalance in these can promote pathological processes, such as dyslipidemia . These metabolic pathways not only provide energy for cellular homeostasis, but also control immune cell functions. Immune cells at rest, use processes such as Krebs cycle and oxidative phosphorylation for ATP generation, but cells with pro-inflammatory phenotype such as M1 macrophages and activated T lymphocytes tend to change to aerobic glycolysis, while M2 macrophages and regulatory T lymphocytes induced in the periphery continue with oxidative phosphorylation. Reprogramming of the metabolic state of immune cells influences the generation of epigenetic changes which lead to functional changes. This cellular metabolic state is affected by systemic metabolism, either by nutrients availability or by signalling pathways induced by each metabolite . These concepts are the basis of innate immunological memory, this phenomenon, also called immune training, is defined by metabolic changes originated after priming with pathogens or sterile stimuli that lead to sustained functional changes orchestrated mainly by epigenetic reprogramming, which are sustained changes in gene expression and cellular physiology, which does not imply permanent changes .An immune cell type that attracts more attention in the immunometabolism area is the macrophages population. Macrophages are phagocytic cells of innate immunity with a broad functional spectrum, from pro-inflammatory to anti-inflammatory phenotypes representing the extremes. Monocytes, cells that develop from bone marrow precursors, travel in bloodstream for a few days, then they migrate to tissue and become macrophages with different phenotypes . Tissue-resident macrophages are long-lived cells derived mostly from erythro-myeloid progenitors that emerge from the yolk sac . The first to emerge are the primitive macrophages, which are not derived from monocytes and seed every tissue. When erythro-myeloid progenitors seed the fetal liver, they generate fetal monocytes that differentiate into macrophages, and represent the most abundant tissue-resident macrophage population . Furthermore, monocytes derived from hematopoietic stem cells emerge from the fetal liver and differentiate into long-lived macrophages, while adult hematopoiesis begins in the bone marrow. Bone marrow -derived monocytes contribute to the different populations of postnatal tissue resident macrophages .Monocytes/ macrophages are recognized because their important roles in regulating homeostasis and immune defense through their inflammatory or tissue repair properties . The importance of metabolism in immune cells for the programming of macrophages with their different functional spectra suggests that metabolic pathways may play a role for long-term functional changes in monocytes and macrophages during immune training . The role of these cells is widely described in obesity, being the main population present in the adipose tissue stromal vascular fraction, where there is an increase in the proliferation of macrophages coupled with the recruitment of circulating monocytes to this tissue. Due to the production of cytokines such as IL-1β, IL-6 and TNF-α, M1 macrophages participate in the low-grade chronic inflammation that characterizes obesity .In past years, it has been shown that when treating monocyte derived macrophages with high concentrations of insulin, glucose and palmitate, characteristic of metabolic syndrome, a different pro-inflammatory phenotype is induced. These cells present surface markers and transcription factors different from classical macrophages and were called metabolically activated macrophages (MMe) . MMe present surface molecules such as CD36, which binds to long chain fatty acids and facilitates their transport in the cell, participating in the use of lipids in muscle, storage of adipose energy and absorption of intestinal fat ; ABCA1 is a cholesterol efflux pump in the elimination pathway of cellular lipids that are then collected by apoA-I, forming high-density lipoproteins (HDL) ; and PLIN2, which is a protein expressed on the lipid droplet membrane . These MMe have been described in metabolic syndrome and have been found in adipose tissue during obesity, performing beneficial and detrimental functions during diet-induced obesity in mice , and in mammary adipose tissue promoting tumorigenesis during obesity . MMe produce pro-inflammatory cytokines, although in a lesser extent than classic M1 macrophages. The expression of their characteristic surface markers, as well as the attenuated inflammatory response, is mainly mediated by the transcription factor PPAR-γ , that could be contributing to the chronic low-grade inflammatory state present in metabolic syndrome and obesity.Due to dietary overload, the metabolites produced by the different metabolic pathways can be used for alternative pathways in organs and tissues, such as adipose tissue, modifying and defining systemic metabolic responses It is not completely clear whether the change from a healthy systemic metabolic state to a pathological one, such as the dyslipidemic state, lead to changes causing immune training influencing polarization to different cell types.The aim of this study was to evaluate if high cholesterol and triglycerides levels, main feature of dyslipidemia, are promoting immune training in peripheral blood cells, functioning as a first stimulus, conditioning monocytes to present a metabolic phenotype and leading them to polarization into metabolically activated macrophages. We found that monocytes with metabolic phenotype expressing CD36, ABCA1 and PLIN2, are present in systemic circulation. In vitro stimulation showed that MMe from patients with dyslipidemia, play a dynamic role with production of pro- and anti-inflammatory cytokines.