Neutrophil extracellular traps enhance early inflammatory response in Sendai virus-induced asthma phenotype

Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase (MPO) in the alveolar space and plasma that peaked on day 2-post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow derived cells to release cytokines that can amplify the inflammatory cascade

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Feedback Amplification of Neutrophil Function

As the first line of innate immune defense, neutrophils need to mount a rapid and robust antimicrobial response. Recent studies implicate various positive feedback amplification processes in achieving that goal. Feedback amplification ensures effective migration of neutrophils in shallow chemotactic gradients, multiple waves of neutrophil recruitment to the site of inflammation, and the augmentation of various effector functions of the cells. We review here such positive feedback loops including intracellular and autocrine processes, paracrine effects mediated by lipid (LTB4), chemokine, and cytokine mediators, and bidirectional interactions with the complement system and with other immune and non-immune cells. These amplification mechanisms are not only involved in antimicrobial immunity but also contribute to neutrophil-mediated tissue damage under pathological conditions. © 2016 Elsevier Ltd

Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathogenic Mechanisms and Clinical Translation

The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn’s Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD

Resolution of inflammation: what Controls its Onset?

The authors would like to acknowledge the funding agencies, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Comissão de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES, Brazil), Fundação do Amparo a Pesquisa de Minas Gerais (FAPEMIG, Brazil), Instituto Nacional de Ciência e Tecnologia (INCT in Dengue), and the European Community’s Seventh Framework Programme (FP7-2007-2013, Timer consortium) under grant agreement HEALTH-F4-2011-281608. MP acknowledges funding from the Wellcome Trust (program 086867/Z/08), the Medical Research Council UK (MR/K013068/1), and the William Harvey Research Foundation

Neutrophil Extracellular Traps in Breast Cancer and Beyond: Current Perspectives on NET Stimuli, Thrombosis and Metastasis, and Clinical Utility for Diagnosis and Treatment

Abstract The formation of neutrophil extracellular traps (NETs), known as NETosis, was first observed as a novel immune response to bacterial infection, but has since been found to occur abnormally in a variety of other inflammatory disease states including cancer. Breast cancer is the most commonly diagnosed malignancy in women. In breast cancer, NETosis has been linked to increased disease progression, metastasis, and complications such as venous thromboembolism. NET-targeted therapies have shown success in preclinical cancer models and may prove valuable clinical targets in slowing or halting tumor progression in breast cancer patients. We will briefly outline the mechanisms by which NETs may form in the tumor microenvironment and circulation, including the crosstalk between neutrophils, tumor cells, endothelial cells, and platelets as well as the role of cancer-associated extracellular vesicles in modulating neutrophil behavior and NET extrusion. The prognostic implications of cancer-associated NETosis will be explored in addition to development of novel therapeutics aimed at targeting NET interactions to improve outcomes in patients with breast cancer

Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease:a review

Abstract Background Cystic Fibrosis (CF) is a devastating genetic disease characterised primarily by unrelenting lung inflammation and infection resulting in premature death and significant morbidity. Neutrophil Extracellular Traps (NETs) are possibly key to inflammation in the disease. This review aims to draw together existing research investigating NETs in the context of a dysfunctional innate immune system in CF. Main body NETs have a limited anti-microbial role in CF and studies have shown they are present in higher numbers in CF airways and their protein constituents correlate with lung function decline. Innate immune system cells express CFTR and myeloid-specific CFTR KO mice have greater neutrophil recruitment and higher pro-inflammatory cytokine production to both sterile and bacterial inflammatory challenges. CFTR KO neutrophils have impaired anti-microbial capacity and intrinsic abnormalities in the pH of their cytoplasm, abnormal protein trafficking, increased neutrophil elastase and myeloperoxidase function, and decreased hypochlorite concentrations in their phagolysosomes. Furthermore, neutrophils from CF patients have less intrinsic apoptosis and may be therefore more likely to make NETs. CFTR KO macrophages have high intraphagolysosomal pH and increased toll-like receptor 4 on their cell surface membranes, which inhibit their anti-microbial capacity and render them hyper-responsive to inflammatory stimuli, respectively. Pharmacological treatments for CF target these intrinsic abnormalities of immune dysfunction. Emerging evidence suggests that the absence of CFTR from neutrophils affects NETosis and the interaction of NETs with macrophages. Conclusion Current evidence suggests that NETs contribute to inflammation and lung destruction rather than working effectively in their anti-microbial capacity. Further studies focussing on the pro-inflammatory nature of NET constituents are required to identify the exact mechanistic role of NETs in CF and potential therapeutic interventions

Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.British Heart Foundation Programme Grant (CS, PE); British Heart Foundation Project Grants PG/09/067/27901 (AB, VR), PG/13/55/30365 (LW, SF), PG/14/38/30862 (CR, VR), PG/16/44/32146 (JJ, EKT, SF); British Heart Foundation Studentship FS/14/8/30605 (BW, VR); MRC Fellowship MR/K023977/1 (RB); and European Union’s Horizon 2020 Marie Skłodowska-Curie Innovative Training Network, TRAIN 721532 (CN)