Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency

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dc.contributor.authorGul, Ersin
dc.contributor.authorSayar, Esra Hazar
dc.contributor.authorGungor, Bilgi
dc.contributor.authorEroglu, Fehime Kara
dc.contributor.authorSurucu, Naz
dc.contributor.authorKeles, Sevgi
dc.contributor.authorGuner, Sukru Nail
dc.date.accessioned2024-02-23T14:12:30Z
dc.date.available2024-02-23T14:12:30Z
dc.date.issued2018
dc.departmentNEÜen_US
dc.description.abstractBackground: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). Objective: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Methods: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Results: Type I and III IFNsignatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed fromthe accumulation of DNA in the cytoplasm of ATand Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of theirNETotic tendencies. Asimilar phenomenonwas also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-alpha. Conclusions: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.en_US
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [315S125, 115S430]en_US
dc.description.sponsorshipThis project was partially supported by the Scientific and Technological Research Council of Turkey (TUBITAK) (grant nos. 315S125 and 115S430).en_US
dc.identifier.doi10.1016/j.jaci.2017.10.030
dc.identifier.endpage257en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue1en_US
dc.identifier.pmid29155101en_US
dc.identifier.scopus2-s2.0-85038818197en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage246en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2017.10.030
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12080
dc.identifier.volume142en_US
dc.identifier.wosWOS:000437837500027en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby-Elsevieren_US
dc.relation.ispartofJournal Of Allergy And Clinical Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectPrimary Immunodeficienciesen_US
dc.subjectAutoinflammationen_US
dc.subjectAtaxia Telangiectasiaen_US
dc.subjectArtemis Deficiencyen_US
dc.subjectType I Ifnen_US
dc.subjectInterferonopathyen_US
dc.subjectNeutrophil Extracellular Trapsen_US
dc.subjectNetosisen_US
dc.titleType I IFN-related NETosis in ataxia telangiectasia and Artemis deficiencyen_US
dc.typeArticleen_US

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