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

Gül, Ersin; Sayar, Esra Hazar; Gungor, Bilgi; Eroğlu, Fehime Kara; Surucu, Naz; Keleş, Sevgi; Güner, Şükrü Nail; Fındık, Sıddıka; Alpdundar, Esin; Ayanoğlu, İhsan Cihan; Kayaoğlu, Başak; Geckin, Büsra; Sanli, Hatice Asena; Kahraman, Tamer; Yakıcıer, Cengiz; Müftüoğlu, Meltem; Oğuz, Berna; Çağdaş, Deniz; Gürsel, İhsan; Özen, Seza; Reisli, İsmail; Gürsel, Mayda

doi:10.1016/j.jaci.2017.10.030

Cited by 51 publications

(34 citation statements)

References 66 publications

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“…In our infection models of increased susceptibility to TB, NETosis was completely abrogated in the absence of type I IFN signalling, which correlated with better control of infection and less tissue damage. Similarly, previous in vitro studies have reported that neutrophils produce NETs when exposed to plasma samples from patients with autoimmune disorders showing elevated levels of type I IFN or exogeneous IFN-α 69 , 70 . These data suggested that type I IFN primes neutrophils for the formation of NETs.…”

Section: Discussionsupporting

confidence: 59%

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

et al. 2020

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Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.

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Section: Discussionsupporting

confidence: 59%

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

et al. 2020

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“…All mechanisms stated above contribute to a more aggravated type-IIFN response and exacerbate disease. A similar phenomenon can be observed in SAVI, ataxia telangiectasia (AT) and Artemis deficiency (183). However, compared with SAVI, DCs in SLE can prime T-cell maturation significantly and increasing secretion of pro-inflammatory cytokines, such as IL-6 and TNFα can also lead to activation of adaptive immunity (Figure 4A).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasessupporting

confidence: 63%

“…AT patients usually show neurodegenerative defects (especially ataxia) complicated with telangiectasia on their eyes or body, deficiency of adaptive immune cells, and predisposition to cancer (201). Nevertheless, up-regulation of expression of type-I IFN can also be found in AT patients and mice, causing them to be prone to autoimmune diseases (36, 183,202). This syndrome is related to p53-mediated senescence but also the chronic inflammation mediated by the cGAS-STING pathway which engages cytosolic uncombined broken gDNA caused by ATM dysfunction (127).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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“…Recessive mutations in this gene cause Omenn syndrome, a severe combined immunodeficiency associated with increased cellular radiosensitivity due to a defect in V(D)J recombination that leads to early arrest of both B and T cell maturation [15]. A recent functional study demonstrated that Artemis-deficient cells have type I and type III IFN signatures due to the chronic accumulation of DNA [16].…”

Section: Towards a Molecular Stratification Of Sle—first Steps: The Rmentioning

confidence: 99%

New Attempts to Define and Clarify Lupus

Alarcón‐Riquelme

2019

Curr Rheumatol Rep

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Purpose of Review The purpose is to discuss the advances that genetics and genomics have provided to better understand the molecular mechanisms behind SLE and how to solve its heterogeneity. I propose new ideas that can help us stratify lupus in order to find the best therapies for each patient, and the idea of substituting clinical diagnosis with molecular diagnosis according to their molecular patterns, an idea that may not only include lupus but also other diseases. Recent Findings The study of rare mutations may provide insight into groups of lupus patients where type I interferon signature is important and help understand those with an atypical clinical presentation. Recent papers used longitudinal blood transcriptome data correlating with disease activity scores to stratify lupus into molecular clusters. The implication of neutrophils in the risk to develop nephritis was established, but also that neutrophils and lymphocytes may correlate with activity differentiating the mechanisms of flares and separating patients into clinically separate groups. Summary The role of type I interferon signature is important; however, the stratification of SLE patients according to the genes and cellular compartments being modulated during disease activity may be even more important to define those patients who may benefit the most with new anti-type I IFN receptor therapies.

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

Cited by 51 publications

References 66 publications

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

New Attempts to Define and Clarify Lupus

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