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      Eosinophil Extracellular Traps and Inflammatory Pathologies—Untangling the Web!

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          Abstract

          Eosinophils are an enigmatic white blood cell, whose immune functions are still under intense investigation. Classically, the eosinophil was considered to fulfill a protective role against parasitic infections, primarily large multicellular helminths. Although eosinophils are predominantly associated with parasite infections, evidence of a role for eosinophils in mediating immunity against bacterial, viral, and fungal infections has been recently reported. Among the mechanisms by which eosinophils are proposed to exert their protective effects is the production of DNA-based extracellular traps (ETs). Remarkably, DNA serves a role that extends beyond its biochemical function in encoding RNA and protein sequences; it is also a highly effective substance for entrapment of bacteria and other extracellular pathogens, and serves as valuable scaffolding for antimicrobial mediators such as granule proteins from immune cells. Extracellular trap formation from eosinophils appears to fulfill an important immune response against extracellular pathogens, although overproduction of traps is evident in pathologies. Here, we discuss the discovery and characterization of eosinophil extracellular traps (EETs) in response to a variety of stimuli, and suggest a role for these structures in the pathogenesis of disease as well as the establishment of autoimmunity in chronic, unresolved inflammation.

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          The eosinophil.

          Eosinophils have been considered end-stage cells involved in host protection against parasites. However, numerous lines of evidence have now changed this perspective by showing that eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, we summarize the biology of eosinophils, focusing on the growing properties of eosinophil-derived products, including the constituents of their granules as well as the mechanisms by which they release their pleiotropic mediators. We examine new views on the role of eosinophils in homeostatic function, including developmental biology and innate and adaptive immunity (as well as interaction with mast cells and T cells). The molecular steps involved in eosinophil development and trafficking are described, with special attention to the important role of the transcription factor GATA-1, the eosinophil-selective cytokine IL-5, and the eotaxin subfamily of chemokines. We also review the role of eosinophils in disease processes, including infections, asthma, and gastrointestinal disorders, and new data concerning genetically engineered eosinophil-deficient mice. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
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            Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis.

            During the systemic inflammatory response of severe sepsis, neutrophils accumulate in the liver microcirculation, but their functional significance is largely unknown. We show that neutrophils migrate to liver sinusoids during endotoxemia and sepsis where they exert protective effects by releasing neutrophil extracellular traps (NETs), which are DNA-based structures that capture and eliminate microbes. NETs released into the vasculature ensnare bacteria from the bloodstream and prevent dissemination. NET production requires platelet-neutrophil interactions and can be inhibited by platelet depletion or disruption of integrin-mediated platelet-neutrophil binding. During sepsis, NET release increases bacterial trapping by 4-fold (beyond the basal level provided by resident intravascular macrophages). Blocking NET formation reduces the capture of circulating bacteria during sepsis, resulting in increased dissemination to distant organs. Thus, NETs ensnare circulating bacteria and provide intravascular immunity that protects against bacterial dissemination during septic infections. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Eosinophils: biological properties and role in health and disease.

              Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
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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
                26 November 2018
                2018
                : 9
                : 2763
                Affiliations
                [1] 1Department of Medicine, McMaster University and St Joseph's Healthcare , Hamilton, ON, Canada
                [2] 2Department of Medicine, Alberta Respiratory Centre, University of Alberta , Edmonton, AB, Canada
                [3] 3Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine , Akita, Japan
                Author notes

                Edited by: Moncef Zouali, Institut National de la Santé et de la Recherche Médicale (INSERM), France

                Reviewed by: Hrishikesh Pandit, National Cancer Institute at Frederick, United States; Ian Dransfield, University of Edinburgh, United Kingdom

                *Correspondence: Manali Mukherjee mukherj@ 123456mcmaster.ca

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

                Article
                10.3389/fimmu.2018.02763
                6275237
                30534130
                5e171b09-9bca-407b-a708-bf5e1f366e30
                Copyright © 2018 Mukherjee, Lacy and Ueki.

                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.

                History
                : 16 July 2018
                : 09 November 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 79, Pages: 10, Words: 8096
                Categories
                Immunology
                Review

                Immunology
                eosinophils,degranulation,extracellular traps,etosis,cytolysis,airways,sputum
                Immunology
                eosinophils, degranulation, extracellular traps, etosis, cytolysis, airways, sputum

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