Type I IFN related NETosis in Ataxia Telangiectasia and Artemis deficiency

Publication date: Available online 16 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Ersin Gul, Esra Hazar Sayar, Bilgi Gungor, Fehime Kara Eroglu, Naz Surucu, Sevgi Keles, Sukru Nail Guner, Sıddıka Fındık, Esin Alpdündar, Ihsan Cihan Ayanoglu, Basak Kayaoglu, Busra Nur Geçkin, Hatice Asena Sanli, Tamer Kahraman, Cengiz Yakicier, Meltem Muftuoglu, Berna Oguz, Deniz Nazire Cagdas Ayvaz, Ihsan Gursel, Seza Ozen, Ismail Reisli, Mayda Gursel
BackgroundPathological inflammatory syndromes of unknown etiology are commonly observed in Ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in STING-associated vasculopathy in infancy (SAVI) patients.ObjectiveTo test the hypothesis that the inflammation associated manifestations observed in AT and Artemis deficient patients stem from increased type I IFN signature leading to neutrophil mediated pathological damage.MethodsCytokine/protein signatures were determined by ELISA, cytometric bead array or by qPCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells was 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.ResultsType-I and III interferon signatures were elevated in plasma and peripheral blood cells of AT, Artemis deficient and SAVI patients. Chronic interferon production stemmed from accumulation of DNA in cytoplasm of AT and Artemis deficient cells. Neutrophils isolated from patients spontaneously produced neutrophil extracellular traps (NETs) and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFNα.ConclusionType I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in AT, Artemis deficient and SAVI patients. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.

Graphical abstract

Teaser

Enhanced type I IFN response observed in AT, Artemis deficiency and SAVI, exert tissue damage through neutrophil-driven chronic processes, providing a common target to manage inflammatory syndromes in diseases with active type I IFN signature.


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