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      Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

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          Abstract

          Neutrophil granulocytes, also called polymorphonuclear leukocytes (PMNs), extrude molecular lattices of decondensed chromatin studded with histones, granule enzymes, and antimicrobial peptides that are referred to as neutrophil extracellular traps (NETs). NETs capture and contain bacteria, viruses, and other pathogens. Nevertheless, experimental evidence indicates that NETs also cause inflammatory vascular and tissue damage, suggesting that identifying pathways that inhibit NET formation may have therapeutic implications. Here, we determined that neonatal NET-inhibitory factor (nNIF) is an inhibitor of NET formation in umbilical cord blood. In human neonatal and adult neutrophils, nNIF inhibits key terminal events in NET formation, including peptidyl arginine deiminase 4 (PAD4) activity, neutrophil nuclear histone citrullination, and nuclear decondensation. We also identified additional nNIF-related peptides (NRPs) that inhibit NET formation. nNIFs and NRPs blocked NET formation induced by pathogens, microbial toxins, and pharmacologic agonists in vitro and in mouse models of infection and systemic inflammation, and they improved mortality in murine models of systemic inflammation, which are associated with NET-induced collateral tissue injury. The identification of NRPs as neutrophil modulators that selectively interrupt NET generation at critical steps suggests their potential as therapeutic agents. Furthermore, our results indicate that nNIF may be an important regulator of NET formation in fetal and neonatal inflammation.

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          Most cited references47

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.

            It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
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              Points of control in inflammation.

              Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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                Author and article information

                Contributors
                Journal
                J Clin Invest
                J. Clin. Invest
                J Clin Invest
                The Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                6 September 2016
                3 October 2016
                3 January 2017
                : 126
                : 10
                : 3783-3798
                Affiliations
                [1 ]Department of Pediatrics/Neonatology,
                [2 ]Program in Molecular Medicine,
                [3 ]Division of Vascular Surgery,
                [4 ]Department of Pathology, and
                [5 ]Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
                [6 ]Center for Thrombosis and Hemostasis, University of Mainz, Mainz, Germany.
                [7 ]Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA.
                Author notes
                Address correspondence to: Christian Con Yost, Pediatrics, University of Utah School of Medicine, Williams Building, 295 Chipeta Way, Salt Lake City, Utah 84108, USA. Phone: 801.581.7052; E-mail: christian.yost@ 123456u2m2.utah.edu .
                Author information
                http://orcid.org/0000-0001-9033-3623
                Article
                PMC5096809 PMC5096809 5096809 83873
                10.1172/JCI83873
                5096809
                27599294
                57563825-881a-44fd-b782-8a230980e081
                Copyright © 2016, American Society for Clinical Investigation
                History
                : 22 July 2015
                : 28 July 2016
                Categories
                Research Article

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