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Immunometabolic adaptation of tissue resident macrophages in health and disease


The growing interest in Immunometabolism is fueled by the global obesity epidemic and obesity-induced inflammation is a risk factor for several chronic pathologies and diseases. The field of Immunometabolism is the new frontier for Immunology as it integrates the historically distinct disciplines of Metabolism and Immunology. Studies on macrophage metabolic adaptation largely relies in the investigation of bone marrow derived macrophages and a major gap exists between metabolic regulation of in vitro generated bone marrow macrophages and tissue resident macrophages. The biochemical activities occurring in macrophages are linked to its function and ultimately to mitochondria morphology. Systemic and tissue-derived cues shape macrophage metabolism and mitochondria morphology through fission/fusion events, which orchestrates the overall cellular metabolism and how mitochondria function. Macrophages must rapidly alter their metabolism according to extrinsic cues such as cytokines and microbial products, to acquire different phenotypes and functional states necessary for the downstream function. Activated macrophages have increased metabolic demands closely linked to mitochondria bioenergetics. However, in macrophages, almost nothing is known about the metabolic regulation of these cells within specific tissues, such as in the adipose tissue or brain (microglia) both under physiologic and pathologic circumstances. In general, the proposal is centered on the hypothesis that cellular metabolic pathways (glycolysis, lipolysis, lipogenesis, biosynthesis and degradation of amino acids, transport of molecules by SLCs, among others) and tissue-derived factors orchestrate the function of tissue resident macrophages. The overall goal is to determine how tissue resident macrophages adapt their metabolism to fulfill their function during health and disease. For this, we will (i) evaluate how mitochondria dynamics regulates macrophage phenotype and function, (ii) investigate the role of key transcription factors such as AHR and HIF-1±, and also the metabolic sensor mTOR, in the regulation of macrophage metabolism, (iii) determine the spectrum of macrophage phenotypes in the adipose tissue by single cell RNA sequencing, (iv) describe the SLCs involved in macrophage response against infectious agents and (v) analyze the involvement of tissue derived factors, such as leptin and FAHFAs in the phenotype and function of macrophages and their importance for adipose tissue inflammation-induced insulin resistance and microglia activation during obesity. This unpaved area of research will bring new insights into the field of immunometabolism to further our knowledge into the immunometabolic regulation of tissue resident macrophages. This proposal offers new insights into how macrophage metabolic adaptation regulates the outcomes of auto-inflammatory, metabolic and infectious diseases with great potential for patient wellbeing, as macrophage metabolism is linked to virtually every acute and chronic disease. Findings from this proposal could lead to the discovery of still unknown pathways and possibly novel treatments for inflammatory diseases. (AU)

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