The type I interferonopathies: 10 years on

Crow, Yanick J.; Stetson, Daniel B.

doi:10.1038/s41577-021-00633-9

Cited by 264 publications

(209 citation statements)

References 138 publications

(156 reference statements)

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“…The description of the novel type I interferonopathy SAVI [1,2,50] thus indicated that STING1 gain-of-function mutations led to a severe Mendelian inflammatory ILD. These findings suggest a potential role for STING homeostasis in ILD.…”

Section: Historical Descriptionmentioning

confidence: 99%

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Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

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Section: Historical Descriptionmentioning

confidence: 99%

“…Type I interferonopathies are a sub-group of Mendelian autoinflammatory diseases characterized by an overactivation of the type I interferon (IFN) pathway [1]. Under normal circumstances, IFNs are potent antiviral cytokines produced by cells when they sense foreign nucleic acids [2].…”

Section: Introductionmentioning

confidence: 99%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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“…Interferon is a group of signal proteins synthesized and released by host cells in response to stress and infections. Interferon exists widely in human and other animal organisms with highly species specifictiy (Crow and Stetson, 2021). According to the types of corresponding receptors, interferon can be divided into three types: IFN-I, type II interferon (IFN-II), and type III interferon (IFN-III; Hervas-Stubbs et al, 2011;Stanifer et al, 2019).…”

Section: Rna Modifications In Regulating Ifn Signaling Pathwaymentioning

confidence: 99%

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

et al. 2022

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Posttranscriptional modifications have been implicated in regulation of nearly all biological aspects of cellular RNAs, from stability, translation, splicing, nuclear export to localization. Chemical modifications also have been revealed for virus derived RNAs several decades before, along with the potential of their regulatory roles in virus infection. Due to the dynamic changes of RNA modifications during virus infection, illustrating the mechanisms of RNA epigenetic regulations remains a challenge. Nevertheless, many studies have indicated that these RNA epigenetic marks may directly regulate virus infection through antiviral innate immune responses. The present review summarizes the impacts of important epigenetic marks on viral RNAs, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2ʹ-O-methylation (2ʹ-O-Methyl), and a few uncanonical nucleotides (A-to-I editing, pseudouridine), on antiviral innate immunity and relevant signaling pathways, while highlighting the significance of antiviral innate immune responses during virus infection.

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“…During acute immune responses, IFN-I activation is usually beneficial to the host by providing transcriptional changes that allow the orchestration of an efficient response. However, when this activation persists, it becomes detrimental and is associated with chronic diseases (Crow and Stetson, 2021).…”

Section: Sensing Of Nucleic Acids By Cellular Receptors Activates The...mentioning

confidence: 99%

“…This model has been validated by in vitro experiment, mouse models and clinical data. Indeed, higher levels of circulating IFN-I in mouse models and in patients with mutations in gene encoding DNases and RNAses were detected (Crow and Stetson, 2021). In addition to this, organelles and genome integrity also play a critical part in safeguard mechanisms.…”

Section: Cytosolic Accumulation Of Self-nucleic Acids Allows Activati...mentioning

confidence: 99%

Type-I Interferon Signaling in Fanconi Anemia

Landelouci

Sinha

Pépin

2022

Front. Cell. Infect. Microbiol.

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Fanconi Anemia (FA) is a genome instability syndrome caused by mutations in one of the 23 repair genes of the Fanconi pathway. This heterogenous disease is usually characterized by congenital abnormalities, premature ageing and bone marrow failure. FA patients also show a high predisposition to hematological and solid cancers. The Fanconi pathway ensures the repair of interstrand crosslinks (ICLs) DNA damage. Defect in one of its proteins prevents functional DNA repair, leading to the accumulation of DNA breaks and genome instability. Accumulating evidence has documented a close relationship between genome instability and inflammation, including the production of type-I Interferon. In this context, type-I Interferon is produced upon activation of pattern recognition receptors by nucleic acids including by the cyclic GMP-AMP synthase (cGAS) that detects DNA. In mouse models of diseases displaying genome instability, type-I Interferon response is responsible for an important part of the pathological symptoms, including premature aging, short stature, and neurodegeneration. This is illustrated in mouse models of Ataxia-telangiectasia and Aicardi-Goutières Syndrome in which genetic depletion of either Interferon Receptor IFNAR, cGAS or STING relieves pathological symptoms. FA is also a genetic instability syndrome with symptoms such as premature aging and predisposition to cancer. In this review we will focus on the different molecular mechanisms potentially leading to type-I Interferon activation. A better understanding of the molecular mechanisms engaging type-I Interferon signaling in FA may ultimately lead to the discovery of new therapeutic targets to rescue the pathological inflammation and premature aging associated with Fanconi Anemia.

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The type I interferonopathies: 10 years on

Cited by 264 publications

References 138 publications

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

Type-I Interferon Signaling in Fanconi Anemia

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