Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity

Agraz‐Cibrián, Juan Manuel; Giraldo, Diana M.; Fafutis‐Morris, Mary; Urcuqui-Inchima, Silvio

doi:10.1016/j.virusres.2016.11.033

Cited by 32 publications

(26 citation statements)

References 114 publications

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“…MPO can also cause oxidative damage to viruses upon neutrophil oxidative burst and degranulation ( 45 ). Lately, the antiviral effects of NETs have been implicated ( 46 ). In the present study we observed that serine proteases (such as HNE) play a major role in the virucidal function of neutrophils against PUUV.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells

et al. 2018

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Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection in vitro. These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells

et al. 2018

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“…This review will focus on NET participation in microbial infections, autoimmunity, and metabolic disorders. A detailed description of the mechanisms involved in NET formation is beyond the scope of this work, but additional reviews can be found elsewhere ( 30 ). However, it is important to highlight high-mobility group box 1 (HMGB1) protein-expressing platelets as major endogenous inducers of NET formation, not only during infectious processes but also in sterile inflammation ( 31 , 32 ).…”

Section: Definition Mechanisms and Functionsmentioning

confidence: 99%

Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview

et al. 2017

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In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6–8 h, and in tissue, where they can last up to 7 days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy three to five times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL37, peptidoglycan-binding proteins, and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2–4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5–60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory, and metabolic diseases.

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“…(74) Recently, the formation of neutrophil extracellular traps (NETs) by vitamin D was explored; the production of these networks of extracellular fibers composed of DNA, histones, and enzymes that function to immobilize pathogens were enhanced by 1,25D. (75) However, the NETs-like structures were not verified to be bona fide NETs. Moreover, 1,25D was reported to augment neutrophil killing of Streptococcus pneumoniae and also to lower inflammatory cytokine production by inducing the expression of the anti-inflammatory cytokine IL-4 and suppressor of cytokine signaling (SOCS) proteins.…”

Section: Vitamin D and Granulocyte Biologymentioning

confidence: 99%

Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory

et al. 2020

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Regulation of immune function continues to be one of the most well-recognized extraskeletal actions of vitamin D. This stemmed initially from the discovery that antigen presenting cells such as macrophages could actively metabolize precursor 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D). Parallel observation that activated cells from the immune system expressed the intracellular vitamin D receptor (VDR) for 1,25D suggested a potential role for vitamin D as a localized endogenous modulator of immune function. Subsequent studies have expanded our understanding of how vitamin D exerts effects on both the innate and adaptive arms of the immune system. At an innate level, intracrine synthesis of 1,25D by macrophages and dendritic cells stimulates expression of antimicrobial proteins such as cathelicidin, as well as lowering intracellular iron concentrations via suppression of hepcidin. By potently enhancing autophagy, 1,25D may also play an important role in combatting intracellular pathogens such as M. tuberculosis and viral infections. Local synthesis of 1,25D by macrophages and dendritic cells also appears to play a pivotal role in mediating T-cell responses to vitamin D, leading to suppression of inflammatory T helper (Th)1 and Th17 cells, and concomitant induction of immunotolerogenic Tregulatory responses. The aim of this review is to provide an update on our current understanding of these prominent immune actions of vitamin D, as well as highlighting new, less well-recognized immune effects of vitamin D. The review also aims to place this mechanistic basis for the link between vitamin D and immunity with studies in vivo that have explored a role for vitamin D supplementation as a strategy for improved immune health. This has gained prominence in recent months with the global coronavirus disease 2019 health crisis and highlights important new objectives for future studies of vitamin D and immune function.

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Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity

Cited by 32 publications

References 114 publications

Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells

Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells

Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview

Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory

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