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      Adverse Husbandry of Maraena Whitefish Directs the Immune System to Increase Mobilization of Myeloid Cells and Proinflammatory Responses

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          Abstract

          Adverse life circumstances evoke a common “conserved transcriptional response to adversity” (CTRA) in mammalian leukocytes. To investigate whether this pattern is preserved in lower vertebrates, maraena whitefish ( Coregonus maraena) were exposed for 9 days to different stocking densities: ~10 kg/m 3 (low density), ~33 kg/m 3 (moderate), ~60 kg/m 3 (elevated), and ~100 kg/m 3 (high). Transcriptome profiling in the liver and kidney of individuals from each group suggested that crowding conditions activate stress-related signaling and effector pathways. Remarkably, about one-quarter of the genes differentially expressed under crowding conditions were involved in the activation of immune pathways such as acute-phase response and interleukin/ TNF signaling attended by the simultaneous reduction of antiviral potency. Network analysis confirmed the complex interdigitation of immune- and stress-relevant pathways with interleukin-1 playing a central role. Antibody-based techniques revealed remarkable changes in the blood composition of whitefish and demonstrated the correlation between increasing stocking densities and elevated number of myeloid cells together with the increased phagocytic activity of peripheral blood leukocytes. In line with current studies in mammals, we conclude that crowding stress triggers in whitefish hallmarks of a CTRA, indicating that the stress-induced molecular mechanisms regulating the immune responses not only are conserved within mammals but were established earlier in evolution.

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          Reciprocal regulation of the neural and innate immune systems.

          Innate immune responses are regulated by microorganisms and cell death, as well as by a third class of stress signal from the nervous and endocrine systems. The innate immune system also feeds back, through the production of cytokines, to regulate the function of the central nervous system (CNS), and this has effects on behaviour. These signals provide an extrinsic regulatory circuit that links physiological, social and environmental conditions, as perceived by the CNS, with transcriptional 'decision-making' in leukocytes. CNS-mediated regulation of innate immune responses optimizes total organism fitness and provides new opportunities for therapeutic control of chronic infectious, inflammatory and neuropsychiatric diseases.
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            How stress influences the immune response.

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              Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis.

              Across a variety of adverse life circumstances, such as social isolation and low socioeconomic status, mammalian immune cells have been found to show a conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes. The present study examines whether such effects might stem in part from the selective up-regulation of a subpopulation of immature proinflammatory monocytes (Ly-6c(high) in mice, CD16(-) in humans) within the circulating leukocyte pool. Transcriptome representation analyses showed relative expansion of the immature proinflammatory monocyte transcriptome in peripheral blood mononuclear cells from people subject to chronic social stress (low socioeconomic status) and mice subject to repeated social defeat. Cellular dissection of the mouse peripheral blood mononuclear cell transcriptome confirmed these results, and promoter-based bioinformatic analyses indicated increased activity of transcription factors involved in early myeloid lineage differentiation and proinflammatory effector function (PU.1, NF-κB, EGR1, MZF1, NRF2). Analysis of bone marrow hematopoiesis confirmed increased myelopoietic output of Ly-6c(high) monocytes and Ly-6c(intermediate) granulocytes in mice subject to repeated social defeat, and these effects were blocked by pharmacologic antagonists of β-adrenoreceptors and the myelopoietic growth factor GM-CSF. These results suggest that sympathetic nervous system-induced up-regulation of myelopoiesis mediates the proinflammatory component of the leukocyte CTRA dynamic and may contribute to the increased risk of inflammation-related disease associated with adverse social conditions.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                23 December 2016
                2016
                : 7
                : 631
                Affiliations
                [1] 1Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health , Greifswald-Insel Riems, Germany
                [2] 2Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA
                [3] 3Fish Genetics Unit, Institute for Genome Biology, Leibniz Institute for Farm Animal Biology (FBN) , Dummerstorf, Germany
                Author notes

                Edited by: Uday Kishore, Brunel University London, UK

                Reviewed by: Anthony George Tsolaki, Brunel University London, UK; Miki Nakao, Kyushu University, Japan; Dirk Werling, Royal Veterinary College, UK

                *Correspondence: Alexander Rebl, rebl@ 123456fbn-dummerstorf.de

                Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2016.00631
                5179527
                28066440
                319e649c-71e0-4c7e-96d8-37d83fb206ce
                Copyright © 2016 Korytář, Nipkow, Altmann, Goldammer, Köllner and Rebl.

                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) or licensor 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.

                History
                : 13 September 2016
                : 08 December 2016
                Page count
                Figures: 5, Tables: 5, Equations: 0, References: 82, Pages: 14, Words: 10139
                Funding
                Funded by: Ministry of Agriculture, Environment and Consumer Protection Mecklenburg-Western Pomerania
                Award ID: VI-560/730-32614
                Categories
                Immunology
                Original Research

                Immunology
                interleukins,leukocytes,lower vertebrates,salmonid fish,stocking density,transcriptome,welfare
                Immunology
                interleukins, leukocytes, lower vertebrates, salmonid fish, stocking density, transcriptome, welfare

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