Understanding the Entanglement: Neutrophil Extracellular Traps (NETs) in Cystic Fibrosis

Martínez-Alemán, S.; Campos-García, Lizbeth; Palma-Nicolás, José Prisco; Hernández-Bello, Romel; González, Gloria M.; Sánchez-González, Alejandro

doi:10.3389/fcimb.2017.00104

Cited by 70 publications

(45 citation statements)

References 69 publications

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“…Although NETs have potentially beneficial anti-pathogenic functions in respiratory host defenses, protection can easily turn to injury when extensive, unbalanced NET formation occurs. NETs are embedded with potent granule proteins that are capable of killing pathogens but may also, under the right conditions, induce cell death of lung epithelial and endothelial cells (27) and contribute to certain lung diseases such as asthma (28), cystic fibrosis (29), and COPD (30). Little is known regarding the interaction between NETs and specific cells, including AMs.…”

Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition

et al. 2020

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Introduction: Aerobic exercise improves lung inflammation in acute lung injury (ALI), but its mechanism remains unknown. Neutrophil extracellular traps (NETs) play an important role in LPS-induced ALI, and a positive correlation exists between NET formation and proinflammatory macrophage polarization. This study investigated whether aerobic exercise reduces the pro-inflammatory polarization of alveolar macrophages (AMs) by inhibiting the excessive release of NETs and then alleviating the inflammatory response of ALI. Methods: C57BL/6 male mice were randomly divided into four groups: sedentary group (CON), sedentary and extra-pulmonary LPS injection group (LPS), 5-weeks aerobic training intervention and LPS injection group (EXE+LPS), and DNase I plus LPS injection group (DNase+LPS). Twenty-four hours after drug injection, bronchoalveolar lavage fluid (BALF), AM, and lung tissues were obtained to detect inflammatory responses, NET formation, macrophage polarization, and protein activation. In the in vitro study, a murine AM cell line, designated MH-S, was stimulated with LPS, purified NETs, and NETs plus DNase I. Results: EXE+LPS and DNase+LPS mice exhibited reduced neutrophil infiltration, decreased NET release, and lower pro-inflammatory polarization of AM compared with LPS mice. Subsequently, Western blot showed inhibition of the phosphorylation of MAPK and NF-κB proteins of AMs in EXE+LPS and DNase+LPS mice compared with LPS mice. Lastly, stimulation of MH-S cells by NETs revealed a trend for pro-inflammatory cell polarization, with NF-κB protein activation at 8 h and ERK1/2 activation at 1, 2, and 8 h. Conclusions: Aerobic exercise alleviated ALI through NET-induced AM pro-inflammatory polarization involving ERK1/2 and NF-κB signaling.

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Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition

et al. 2020

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“…1 Because many of the antimicrobial contents of neutrophil extracellular traps (NETs) have intrinsic cytotoxic activity, they also have the potential to cause bystander injury to host cells. [3][4][5][6] However, more recent work has demonstrated that NETs also form in response to noninfectious tissue injury. [3][4][5][6] However, more recent work has demonstrated that NETs also form in response to noninfectious tissue injury.…”

Section: Introductionmentioning

confidence: 99%

“…2 In the lung, this has been suspected during infectious exacerbations of cystic fibrosis (CF), chronic pulmonary obstructive disease, bacterial pneumonia, and tuberculosis. [3][4][5][6] However, more recent work has demonstrated that NETs also form in response to noninfectious tissue injury. NETs have been reported to promote inflammation in models of primary lung graft dysfunction (PGD), 7 transfusion-related acute lung injury, 8 and ventilation-induced acute lung injury.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Scozzi

Wang

Liao

et al. 2019

American Journal of Transplantation

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Neutrophil extracellular traps (NETs) have been shown to worsen acute pulmonary injury including after lung transplantation. The breakdown of NETs by DNAse‐1 can help restore lung function, but whether there is an impact on allograft tolerance remains less clear. Using intravital 2‐photon microscopy, we analyzed the effects of DNAse‐1 on NETs in mouse orthotopic lung allografts damaged by ischemia‐reperfusion injury. Although DNAse‐1 treatment rapidly degrades intragraft NETs, the consequential release of NET fragments induces prolonged interactions between infiltrating CD4+ T cells and donor‐derived antigen presenting cells. DNAse‐1 generated NET fragments also promote human alveolar macrophage inflammatory cytokine production and prime dendritic cells for alloantigen‐specific CD4+ T cell proliferation through activating toll‐like receptor (TLR) — Myeloid Differentiation Primary Response 88 (MyD88) signaling pathways. Furthermore, and in contrast to allograft recipients with a deficiency in NET generation due to a neutrophil‐specific ablation of Protein Arginine Deiminase 4 (PAD4), DNAse‐1 administration to wild‐type recipients promotes the recognition of allo‐ and self‐antigens and prevents immunosuppression‐mediated lung allograft acceptance through a MyD88‐dependent pathway. Taken together, these data show that the rapid catalytic release of NET fragments promotes innate immune responses that prevent lung transplant tolerance.

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“…NET primarily identified, produced by neutrophils to kill microorganisms and to defend against pathogens, are demonstrated to be formed also during inflammatory events, as for example, in cystic fibrosis, thrombosis, and chronic obstructive pulmonary disease . In the last years, the list of diseases in which these neutrophil products are demonstrated to be involved was certainly increased and a key role of NET in non‐infective diseases was recently outlined .…”

Section: Discussionmentioning

confidence: 99%

β2-Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes

Marino

Scanzano

Pulze

et al. 2018

Journal of Leukocyte Biology

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This study tests the hypothesis that in isolated human polymorphonuclear leukocytes (PMN) adrenergic ligands can affect neutrophil extracellular trap (NET) formation. We have previously shown that, in PMN, adrenaline (A), through the activation of adrenergic receptors (AR), reduces stimulus-dependent cell activation; we have, therefore, planned to investigate if AR are involved in NET production. PMN were obtained from venous blood of healthy subject. The ability of adrenergic ligands to affect reactive oxygen species (ROS) production, NET production, and cell migration was investigated in cells cultured under resting conditions or after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP), LPS, or IL-8. Stimuli-induced NET production measured as ROS, microscopic evaluation, and elastase production was reverted by A and this effect was blocked by the selective β -AR antagonist ICI-118,551. The stimulus-induced ROS generation and migration was prevented by A and by isoprenaline (ISO), and these effects were counteracted only by ICI-118,551 and not by the other two selective ligands for the β and β -AR. Finally, the presence of the β-ARs on PMN was confirmed, by means of microscopy and flow cytometry. The data of the present study suggest that adrenergic compounds, through the interaction of mainly β -AR, are able to affect neutrophil functions. These data are suggestive of a possible therapeutic role of β -AR ligands (in addition to their classical use), promoting the possible therapeutic relevance of adrenergic system in the modulation of innate immunity proposing their possible use as anti-inflammatory drugs.

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Understanding the Entanglement: Neutrophil Extracellular Traps (NETs) in Cystic Fibrosis

Cited by 70 publications

References 69 publications

Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition

Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

β2-Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes

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