DNA damage rather than type I IFN signaling is the primary mediator of neural dysfunction in Aicardi-Goutières syndrome after RNASEH2 disruption

Neuron ◽  
2021 ◽  
Vol 109 (24) ◽  
pp. 3897-3900
Author(s):  
Martin F. Lavin ◽  
Abrey J. Yeo
Keyword(s):  
Dna Damage ◽  
Type I ◽  
Type I Ifn ◽  
Neural Dysfunction

scholarly journals Pharmacological Targeting of STING-Dependent IL-6 Production in Cancer Cells

2022 ◽  
Vol 9 ◽  
Author(s):  
Sumaiah S. Al-Asmari ◽  
Aleksandra Rajapakse ◽  
Tomalika R. Ullah ◽  
Geneviève Pépin ◽  
Laura V. Croft ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Colony Formation ◽  
Human Cancer ◽  
Type I ◽  
Type I Ifn ◽  
Human Cancer Cells ◽  
Rapid Production ◽  
Nci60 Panel ◽  
Sting Pathway

Activation of the STING pathway upon genotoxic treatment of cancer cells has been shown to lead to anti-tumoral effects, mediated through the acute production of interferon (IFN)-β. Conversely, the pathway also correlates with the expression of NF-κB-driven pro-tumorigenic genes, but these associations are only poorly defined in the context of genotoxic treatment, and are thought to correlate with a chronic engagement of the pathway. We demonstrate here that half of the STING-expressing cancer cells from the NCI60 panel rapidly increased expression of pro-tumorigenic IL-6 upon genotoxic DNA damage, often independent of type-I IFN responses. While preferentially dependent on canonical STING, we demonstrate that genotoxic DNA damage induced by camptothecin (CPT) also drove IL-6 production through non-canonical STING signaling in selected cancer cells. Consequently, pharmacological inhibition of canonical STING failed to broadly inhibit IL-6 production induced by CPT, although this could be achieved through downstream ERK1/2 inhibition. Finally, prolonged inhibition of canonical STING signaling was associated with increased colony formation of MG-63 cells, highlighting the duality of STING signaling in also restraining the growth of selected cancer cells. Collectively, our findings demonstrate that genotoxic-induced DNA damage frequently leads to the rapid production of pro-tumorigenic IL-6 in cancer cells, independent of an IFN signature, through canonical and non-canonical STING activation; this underlines the complexity of STING engagement in human cancer cells, with frequent acute pro-tumorigenic activities induced by DNA damage. We propose that inhibition of ERK1/2 may help curb such pro-tumorigenic responses to DNA-damage, while preserving the anti-proliferative effects of the STING-interferon axis.

scholarly journals Type I Interferon Induction in Cutaneous DNA Damage Syndromes

2021 ◽  
Vol 12 ◽  
Author(s):  
Benjamin Klein ◽  
Claudia Günther
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Nucleic Acids ◽  
Werner Syndrome ◽  
Excision Repair ◽  
Autoimmune Disorders ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

scholarly journals A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Abigail J Morales ◽  
Javier A Carrero ◽  
Putzer J Hung ◽  
Anthony T Tubbs ◽  
Jared M Andrews ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genomic Dna ◽  
Genetic Program ◽  
Inflammasome Activation ◽  
Type I ◽  
Type I Ifn ◽  
Immune Functions ◽  
Murine Macrophages ◽  
Damage Response

Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18. Indeed, following infection with Listeria monocytogenes, DNA-PKcs-deficient murine macrophages produce reduced levels of IL-18 and are unable to optimally stimulate IFN-γ production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR.

scholarly journals Contraction of the type I IFN locus and unusual constitutive expression ofIFN-αin bats

2016 ◽  
Vol 113 (10) ◽  
pp. 2696-2701 ◽  
Author(s):  
Peng Zhou ◽  
Mary Tachedjian ◽  
James W. Wynne ◽  
Victoria Boyd ◽  
Jie Cui ◽  
...  
Keyword(s):  
Dna Damage ◽  
Antiviral Activity ◽  
Clinical Signs ◽  
Constitutive Expression ◽  
Type I ◽  
Type I Ifn ◽  
Highly Pathogenic ◽  
Gene Map ◽  
Flying Fox

Bats harbor many emerging and reemerging viruses, several of which are highly pathogenic in other mammals but cause no clinical signs of disease in bats. To determine the role of interferons (IFNs) in the ability of bats to coexist with viruses, we sequenced the type I IFN locus of the Australian black flying fox,Pteropus alecto, providing what is, to our knowledge, the first gene map of the IFN region of any bat species. Our results reveal a highly contracted type I IFN family consisting of only 10 IFNs, including three functionalIFN-αloci. Furthermore, the threeIFN-αgenes are constitutively expressed in unstimulated bat tissues and cells and their expression is unaffected by viral infection. Constitutively expressedIFN-αresults in the induction of a subset of IFN-stimulated genes associated with antiviral activity and resistance to DNA damage, providing evidence for a unique IFN system that may be linked to the ability of bats to coexist with viruses.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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