Abstract
Immunometabolism emerged as a new frontier of knowledge in search of integration between the historically distinct disciplines of Metabolism and Immunology. Growing interest in this area has been fueled by the global obesity epidemic and by the recent finding that obesity affects the immune system and promotes inflammation. Obesity-induced inflammation causes and aggravates a variety of chronic pathological conditions and diseases. The study of how metabolism affects the immune response and how obesity, by affecting systemic metabolism, modulates metabolism and cellular immune function will provide new mechanisms for the understanding of immunometabolic regulation in different pathological conditions. At the center of this regulation are the transcription factors HIF-1 ± (hypoxia-induced factor) and LXR (hepatic receptor X), as well as metabolic sensors such as mTOR (mammalian target of rapamycin), both complex 1 of mTORC, characterized by Raptor, and complex 2, characterized by Rictor. These proteins modulate important aspects of the metabolism and the cellular immune response, affecting the tissue in which they reside and, consequently, the organism. Changes in systemic physiology, such as in chronic diseases, may affect the regulation of these proteins (HIF-1 ±, LXRs and mTOR), adjusting cellular function to a new metabolic state. Thus, the central hypothesis is that the transcription factors HIF-1 ± and LXRs, as well as mTOR, regulate the metabolism of macrophages and CD4 T cells and, consequently, the inflammatory function of these cells, which can be further modulated by systemic physiological changes, as in obesity and hyperleptinemia. Thus, the central objective is to understand how metabolism regulates the function of macrophages and CD4 T-cell tissue both in physiological conditions and in inflammatory diseases. The research project will be divided into different subprojects to study the importance of these factors in immunometabolic regulation. HIF-1 ± Loxp, LXR ± Loxp and ²Loxp, RictorLoxp and RaptorLoxp and OBRLoxp animals with LysMcre or CD4cre animals will be used for the conditional deletion of these molecules in macrophages or in CD4 T cells. The metabolism, macrophage and CD4 T cell polarization and the inflammatory profile of these cells will be studied both in vitro and in vivo. The animals will be submitted to the hyperlipid diet for induction of obesity, insulin resistance and low grade systemic inflammation, and the inflammatory function and metabolic activity will be analyzed comparatively to lean control animals. Within the different subprojects it is expected that 1) HIF-1 ± is required to induce an inflammatory profile in tissue macrophages by modulating its metabolism, resulting in systemic effects; 2) Activation of LXRs inhibits the activation of macrophages, alter cellular metabolism and decrease polarization to a M1 profile, resulting in less inflammation in adipose tissue and improvement of the metabolic syndrome; 3) Activation of LXRs inhibits the generation of pro-inflammatory CD4 + T cells and, consequently, decreases the severity of inflammatory diseases such as Autoimmune Experimental Encephalitis (EAE); 4) Leptin promotes an increase in glycolytic pathway induction and macrophage polarization to a M1 profile by activation of mTOR; and that 5) obese animals, due to low level systemic inflammation, have a higher predisposition to generate inflammatory responses and, consequently, a higher severity of autoimmune diseases as in EAE. The multi-level interactions between the metabolic and immune systems suggest that pathogenic mechanisms may underlie of complications observed in obesity and offer substantial therapeutic promise. (AU)
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