Cystic fibrosis sputum DNA has NETosis characteristics and neutrophil extracellular trap release is regulated by macrophage migration-inhibitory factor.
Markryan Dwyer,Qiang Shan,Samantha D'Ortona,Rie Maurer,Robert A. Mitchell,Hanne Olesen,Steffen Thiel,Johannes Huebner,Mihaela Gadjeva +8 more
Reads0
Chats0
TLDR
It is suggested that targeting MIF by small molecular inhibitors might reduce the presence of extracellular DNA and serve as an adjunct to the use of antimicrobial drugs that could ultimately reduce bacterial fitness in the lungs during the later stages of CF disease.Abstract:
Neutrophils are the main proinflammatory cell type in chronically infected lungs of cystic fibrosis (CF) patients; however, they fail to effectively clear the colonizing pathogens. Here, we investigated the molecular composition of non-mucoid and mucoid Pseudomonas aeruginosa-induced neutrophil extracellular traps (NETs) in vitro and compared them to the DNA-protein complexes present in the CF sputum. The protein composition of P. aeruginosa-induced NET fragments revealed that irrespective of the inducing stimuli, NET fragments were decorated with a conserved set of proteins. The DNA-protein complexes derived from CF sputum were consistent with NETosis and shared a similar protein signature, suggesting that the majority of the extracellular DNA was NET derived. The ability of polymorphonuclear leukocytes to produce NETs in response to P. aeruginosa was driven by macrophage migration-inhibitory factor (MIF) by promoting mitogen-activated protein kinase. Analysis of 132 CF patient samples revealed that elevated MIF protein levels correlated with poorer lung function. We suggest that targeting MIF by small molecular inhibitors might reduce the presence of extracellular DNA and serve as an adjunct to the use of antimicrobial drugs that could ultimately reduce bacterial fitness in the lungs during the later stages of CF disease.read more
Citations
More filters
Journal ArticleDOI
Neutrophil extracellular traps in immunity and disease
TL;DR: The identification of molecules that modulate the release of NETs has helped to refine the view of the role of neutrophils in immune protection, inflammatory and autoimmune diseases and cancer.
Journal ArticleDOI
Neutrophil extracellular traps in COVID-19.
Yu Zuo,Srilakshmi Yalavarthi,Hui Shi,Hui Shi,Kelsey Gockman,Melanie Zuo,Jacqueline A. Madison,Christopher N. Blair,Andrew G. Weber,Betsy J. Barnes,Betsy J. Barnes,Mikala Egeblad,Robert J. Woods,Yogendra Kanthi,Jason S. Knight +14 more
TL;DR: Sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs, which may contribute to cytokine release and respiratory failure.
Journal ArticleDOI
Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis
Laurent Meijer,Deborah J. Nelson,Vladimir Riazanski,Aida G. Gabdoulkhakova,Geneviève Héry-Arnaud,Rozenn Le Berre,Nadège Loaëc,Nassima Oumata,Hervé Galons,Emmanuel Nowak,L. Guéganton,Guillaume Dorothée,Michaela Prochazkova,Bradford Hall,Ashok B. Kulkarni,Robert D. Gray,Adriano G. Rossi,Véronique Witko-Sarsat,Caroline Norez,Frédéric Becq,Denis Ravel,Dominique Mottier,Gilles Rault +22 more
TL;DR: The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.
Journal ArticleDOI
Neutrophils as emerging therapeutic targets
TL;DR: An overview of the biological and pathological functions of neutrophils is provided, assessing emerging strategies to therapeutically target neutrophil function and agents currently under investigation.
Journal ArticleDOI
Neutrophils and NETs in modulating acute and chronic inflammation
TL;DR: The mechanisms of NET formation are discussed, as well as the apparent paradoxical role of neutrophils and NETs in host defense, chronic inflammation, and tissue disrepair.
References
More filters
Journal ArticleDOI
Neutrophil extracellular traps kill bacteria
Volker Brinkmann,Ulrike Reichard,Christian Goosmann,Beatrix Fauler,Yvonne Uhlemann,David S. Weiss,Yvette Weinrauch,Yvette Weinrauch,Arturo Zychlinsky +8 more
TL;DR: It is described that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria, which degrade virulence factors and kill bacteria.
Journal ArticleDOI
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps
TL;DR: Neutrophil elastase escapes azurophilic granules, translocates to the nucleus, and degrades histones to promote chromatin decondensation necessary for NET formation.
Journal ArticleDOI
Neutrophil Extracellular Traps Contain Calprotectin, a Cytosolic Protein Complex Involved in Host Defense against Candida albicans
Constantin F. Urban,David Ermert,Monika Schmid,Ulrike Abu-Abed,Christian Goosmann,Wolfgang Nacken,Volker Brinkmann,Peter R. Jungblut,Arturo Zychlinsky +8 more
TL;DR: The present investigations confirmed the antifungal activity of calprotectin in vitro and demonstrated that it contributes to effective host defense against C. albicans in vivo.
Journal ArticleDOI
PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps
TL;DR: It is found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing.
Journal ArticleDOI
MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment
Jürgen Bernhagen,Regina M. Krohn,Hongqi Lue,Julia L. Gregory,Alma Zernecke,Rory R. Koenen,Manfred Dewor,Ivan T. Georgiev,Andreas Schober,Lin Leng,Teake Kooistra,Gunter Fingerle-Rowson,Pietro Ghezzi,Robert Kleemann,Shaun R. McColl,Richard Bucala,Michael J. Hickey,Christian Weber +17 more
TL;DR: Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition and displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.