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NETosis 2: The Excitement Continues

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453795 Year: Pages: 362 DOI: 10.3389/978-2-88945-379-5 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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Abstract

NETosis, a form of cell death that manifests by the release of decondensed chromatin to the extracellular space, provides valuable insights into mechanisms and consequences of cellular demise. Because extracellular chromatin can immobilize microbes, the extended nucleohistone network was called a neutrophil extracellular trap (NET), and the process of chromatin release was proposed to serve an innate immune defense function. Extracellular chromatin NETs were initially observed in studies of neutrophils and are most prominent in these types of granulocytes. Subsequent studies showed that other granulocytes and, in a limited way, other cells of the innate immune response may also release nuclear chromatin following certain kinds of stimulation. Variations of NETosis were noted with cells that remain temporarily motile after the release of chromatin. Numerous stimuli for NETosis were discovered, including bacterial breakdown products, inflammatory stimuli, particulate matter, certain crystals, immune complexes and activated thrombocytes. Fundamental explorations into the mechanisms of NETosis observed that neutrophil enzyme activity (PAD4, neutrophil elastase, proteinase 3 and myeloperoxidase) and signal transduction pathways contribute to the regulation of NETosis. Histones in NET chromatin become modified by peptidylarginine deiminase 4 (PAD4) and cleaved at specific sites by proteases, leading to extensive chromatin externalization. In addition, NETs serve for attachment of bactericidal enzymes including myeloperoxidase, leukocyte proteases, and the cathelicidin LL-37. NETs are decorated with proteases and may thus contribute to tissue destruction. However, the attachment of these enzymes to NET-associated supramolecular structures restricts systemic spread of the proteolytic activity. While the benefit of NETs in an infection appears obvious, NETs also participate as key protagonists in various pathologic states. Therefore, it is essential for NETs to be efficiently cleared; otherwise digestive enzymes may gain access to tissues where inflammation takes place. Persistent NET exposure at sites of inflammation may lead to a further complication: NET antigens may provoke acquired immune responses and, over time, could initiate autoimmune reactions, serve as antigen for nuclear autoantibodies and foster DNA immune complex-related inflammation. Neutrophil products and deiminated proteins comprise an important group of autoantigens in musculoskeletal disorders. Aberrant NET synthesis and/or clearance are often associated with inflammatory and autoimmune conditions. Recent evidence also implicates aberrant NET formation in the development of endothelial damage, atherosclerosis and thrombosis. Intravital microscopy provides evidence for conditions that induce NETosis in vivo. Furthermore, NETs can easily be detected in synovial fluid and tissue sections of patients with arthritis and gout. NETosis is thus of interest to researchers who investigate innate immune responses, host-pathogen interactions, chronic inflammatory disorders, cell and vascular biology, biochemistry, and autoimmunity. As we enter the second decade of research on NETosis, it is useful and timely to review the mechanisms and pathways of NET formation, their role in bacterial and fungal defense and their importance as inducers of autoimmune responses.

Chronic inflammation in conditions associated with a deficient clearance of dying and dead cells, their remnants, and intracellular constituents

Authors: --- --- --- --- et al.
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196012 Year: Pages: 73 DOI: 10.3389/978-2-88919-601-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-08-16 10:34:25
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Abstract

In multicellular organisms, states with a high degree of tissue turnover like embryogenesis, development, and adult tissue homeostasis need an instantaneous, tightly regulated and immunologically silent clearance of these dying cells to ensure appropriate development of the embryo and adult tissue remodelling. The proper and swift clearance of apoptotic cells is essential to prevent cellular leakage of damage associated molecular patterns (DAMPs) which would lead to the stimulation of inflammatory cytokine responses. In addition to the clearance of apoptotic cells (efferocytosis), backup mechanisms are required to cope with DAMPs (HMGB-1, DNA, RNA, S100 molecules, ATP and adenosine) and other intracellular material (uric acid, intracellular proteins and their aggregates) released from cells, that were not properly cleared and have entered the stage of secondary necrosis. Furthermore, under certain pathologic conditions (e.g. gout, cancer, diabetes) non-apoptotic cell death may transiently occur (NETosis, necroptosis, pyroptosis) which generates material that also has to be cleared to avoid overloading tissues with non-functional cellular waste. Efficient efferocytosis is therefore indispensable for normal tissue turnover and homeostasis. The characterization of various signalling pathways that regulate this complex and evolutionary conserved process has shed light on new pathogenetic mechanisms of many diseases. Impaired clearance promotes initiation of autoimmunity as well as the perpetuation of chronic inflammation, but may also foster anti-tumor immunity under certain microenvironmental conditions. Immunological tolerance is continuously being challenged by the presence of post-apoptotic remnants in peripheral lymphoid tissues. Besides the autoimmune phenotype of chronic inflammatory rheumatoid disorders a plethora of pathologies have been associated with defects in genes involved in clearance, e.g. atherosclerosis, cancer, gout, diabetes, some forms of blindness, neuropathy, schizophrenia and Alzheimer’s disease. The main goal of this research topic is to collect contributions from various disciplines committed to studying pathogenetic mechanisms of the aforementioned disorders and dealing with alterations in the clearance of dying and dead cells, their remnants, and their constituents that leak out after membrane rupture. Integrating the combined collection of knowledge on efferocytosis and clearance of dead cells and their derived waste from different fields of research in physiology and pathophysiology could improve the molecular understanding of these increasingly prevalent diseases and may ultimately result in new therapeutic strategies.

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