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      Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

      research-article
      1 , 18 , , 1 , 16 , 2 , 16 , 1 , 16 , 3 , 4 , 16 , 1 , 5 , 1 , 1 , 3 , 4 , 1 , 1 , 6 , 7 , 8 , 9 , 10 , 11 , 11 , 12 , 13 , 12 , 11 , 7 , 14 , 1 , 15 , 1 , 3 , 4 , 2 , 17 , 7 , 9 , 17 , 1 , 17 , 19 , ∗∗
      Cell
      Cell Press
      trained innate immunity, β-glucan, innate immune memory, myelopoiesis, inflammation, interleukin-1β, myelosuppression, cholesterol biosynthesis, glycolysis, GM-CSF

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          Summary

          Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.

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          Highlights

          • Trained immunity (TI) modulates hematopoietic progenitors in bone marrow

          • TI is associated with adaptations in cell metabolism in progenitors

          • TI increases expansion of hematopoietic progenitors and myelopoiesis

          • TI promotes beneficial responses to systemic inflammation and chemotherapy

          Abstract

          Modulation of hematopoietic stem and progenitor cells during trained immunity allows a sustained response of myeloid cells to a secondary challenge despite their short lifespan in circulation.

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          Most cited references37

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          Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes.

          Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.

            Bone marrow transplantation is the primary therapy for numerous hematopoietic disorders. The efficiency of bone marrow transplantation depends on the function of long-term hematopoietic stem cells (LT-HSCs), which is markedly influenced by their hypoxic niche. Survival in this low-oxygen microenvironment requires significant metabolic adaptation. Here, we show that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands. We used flow cytometry to identify a unique low mitochondrial activity/glycolysis-dependent subpopulation that houses the majority of hematopoietic progenitors and LT-HSCs. Finally, we demonstrate that Meis1 and Hif-1alpha are markedly enriched in LT-HSCs and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha. These findings reveal an important transcriptional network that regulates HSC metabolism. Copyright 2010 Elsevier Inc. All rights reserved.
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              Chronic interleukin-1 drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal

              Haematopoietic stem cells (HSC) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs via precocious activation of a PU.1-dependent gene program. While this effect is essential for rapid myeloid recovery following acute injury to the bone marrow (BM), chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges like transplantation. Importantly, these damaging effects are transient and fully reversible upon IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and likely underlies deregulated blood homeostasis in chronic inflammation conditions.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                11 January 2018
                11 January 2018
                : 172
                : 1-2
                : 147-161.e12
                Affiliations
                [1 ]Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
                [2 ]Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA
                [3 ]Paul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
                [4 ]German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
                [5 ]DFG-Center for Regenerative Therapies Dresden, Dresden, Germany
                [6 ]Myeloid Cell Biology, LIMES-Institute, University of Bonn, Bonn, Germany
                [7 ]Department of Genomics and Immunoregulation, Life and Medical Science Institute, University of Bonn, Bonn, Germany
                [8 ]Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
                [9 ]Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA, Nijmegen, the Netherlands
                [10 ]Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany
                [11 ]Deep Sequencing Group, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
                [12 ]Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
                [13 ]Lipotype GmbH, Dresden, Germany
                [14 ]PRECISE – Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany
                [15 ]Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
                Author notes
                [16]

                These authors contributed equally

                [17]

                Senior author

                [18]

                Present address: Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden Germany and National Center for Tumor Diseases, Dresden, Germany

                [19]

                Lead Contact

                Article
                S0092-8674(17)31385-5
                10.1016/j.cell.2017.11.034
                5766828
                29328910
                4d3376c8-8d19-4a60-88d0-fc1117a97933
                © 2017 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 April 2017
                : 19 September 2017
                : 16 November 2017
                Categories
                Article

                Cell biology
                trained innate immunity,β-glucan,innate immune memory,myelopoiesis,inflammation,interleukin-1β,myelosuppression,cholesterol biosynthesis,glycolysis,gm-csf

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