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      The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

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          Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.

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          Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron.

          Although iron is required to sustain life, its free concentration and metabolism have to be tightly regulated. This is achieved through a variety of iron-binding proteins including transferrin and ferritin. During infection, bacteria acquire much of their iron from the host by synthesizing siderophores that scavenge iron and transport it into the pathogen. We recently demonstrated that enterochelin, a bacterial catecholate siderophore, binds to the host protein lipocalin 2 (ref. 5). Here, we show that this event is pivotal in the innate immune response to bacterial infection. Upon encountering invading bacteria the Toll-like receptors on immune cells stimulate the transcription, translation and secretion of lipocalin 2; secreted lipocalin 2 then limits bacterial growth by sequestrating the iron-laden siderophore. Our finding represents a new component of the innate immune system and the acute phase response to infection.
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            T cell metabolism drives immunity

            Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.
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              Iron and cancer: more ore to be mined.

              Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.

                Author and article information

                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                22 November 2019
                : 6
                1IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences , Vienna, Austria
                2Department of Neurobiology, Harvard Medical School , Boston, MA, United States
                3FM Kirby Neurobiology Center, Boston Children's Hospital , Boston, MA, United States
                4Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck , Innsbruck, Austria
                5Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck , Innsbruck, Austria
                6Department of Medical Genetics, Life Sciences Institute, University of British Columbia , Vancouver, BC, Canada
                Author notes

                Edited by: Klaus Tenbrock, RWTH Aachen University, Germany

                Reviewed by: Anshu Malhotra, Emory University, United States; Brian M. Polster, University of Maryland, Baltimore, United States

                *Correspondence: Josef M. Penninger josef.penninger@ 123456ubc.ca

                This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Molecular Biosciences

                Copyright © 2019 Cronin, Woolf, Weiss and Penninger.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 203, Pages: 19, Words: 16647
                Funded by: ERA-INFECT
                Award ID: I-3321
                Molecular Biosciences

                bh4, mitochondria, infection, anemia, iron


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