scholarly journals Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response

2020 ◽  
Vol 6 (30) ◽  
pp. eaba3688
Author(s):  
Rekha Dhanwani ◽  
Mariko Takahashi ◽  
Ian T. Mathews ◽  
Camille Lenzi ◽  
Artem Romanov ◽  
...  
Keyword(s):  
Extracellular Dna ◽  
Synthetase Activity ◽  
Type I ◽  
Interferon Β ◽  
Adenosine Deaminases ◽  
Activity Inhibition ◽  
Sam Synthetase ◽  
Cellular Signaling Pathway ◽  
Immune Sensing ◽  
Extracellular Environment

Mechanisms linking immune sensing of DNA danger signals in the extracellular environment to innate pathways in the cytosol are poorly understood. Here, we identify a previously unidentified immune-metabolic axis by which cells respond to purine nucleosides and trigger a type I interferon-β (IFN-β) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dIno, or supplementation of dAdo or dIno stimulates IFN-β. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dIno. dIno is a functional immunometabolite that interferes with the cellular methionine cycle by inhibiting SAM synthetase activity. Inhibition of SAM-dependent transmethylation drives epigenomic hypomethylation and overexpression of immune-stimulatory endogenous retroviral elements that engage cytosolic dsRNA sensors and induce IFN-β. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA–derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-β production.

scholarly journals The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms

2019 ◽  
Vol 117 (2) ◽  
pp. 1160-1166 ◽  
Author(s):  
Julia Lienard ◽  
Esther Nobs ◽  
Victoria Lovins ◽  
Elin Movert ◽  
Christine Valfridsson ◽  
...  
Keyword(s):  
Current Model ◽  
Membrane Integrity ◽  
Mycobacterium Marinum ◽  
Infection Model ◽  
Type I ◽  
Type I Ifn ◽  
Macrophage Infection ◽  
Type Vii Secretion ◽  
Immune Sensing ◽  
Sting Pathway

Following mycobacterial entry into macrophages the ESX-1 type VII secretion system promotes phagosomal permeabilization and type I IFN production, key features of tuberculosis pathogenesis. The current model states that the secreted substrate ESAT-6 is required for membrane permeabilization and that a subsequent passive leakage of extracellular bacterial DNA into the host cell cytosol is sensed by the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) pathway to induce type I IFN production. We employed a collection of Mycobacterium marinum ESX-1 transposon mutants in a macrophage infection model and show that permeabilization of the phagosomal membrane does not require ESAT-6 secretion. Moreover, loss of membrane integrity is insufficient to induce type I IFN production. Instead, type I IFN production requires intact ESX-1 function and correlates with release of mitochondrial and nuclear host DNA into the cytosol, indicating that ESX-1 affects host membrane integrity and DNA release via genetically separable mechanisms. These results suggest a revised model for major aspects of ESX-1–mediated host interactions and put focus on elucidating the mechanisms by which ESX-1 permeabilizes host membranes and induces the type I IFN response, questions of importance for our basic understanding of mycobacterial pathogenesis and innate immune sensing.

NLRP3 inflammasome in ischemic stroke: As possible therapeutic target

2019 ◽  
Vol 14 (6) ◽  
pp. 574-591 ◽  
Author(s):  
Masoumeh Alishahi ◽  
Maryam Farzaneh ◽  
Farhoodeh Ghaedrahmati ◽  
Armin Nejabatdoust ◽  
Alireza Sarkaki ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Current Evidence ◽  
Related Factor ◽  
Type I ◽  
Micro Rnas ◽  
Extracellular Environment ◽  
Inflammasome Inhibitors

Inflammation is a devastating pathophysiological process during stroke, a devastating disease that is the second most common cause of death worldwide. Activation of the NOD-like receptor protein (NLRP3)-infammasome has been proposed to mediate inflammatory responses during ischemic stroke. Briefly, NLRP3 inflammasome activates caspase-1, which cleaves both pro-IL-1 and pro-IL-18 into their active pro-inflammatory cytokines that are released into the extracellular environment. Several NLRP3 inflammasome inhibitors have been promoted, including small molecules, type I interferon, micro RNAs, nitric oxide, and nuclear factor erythroid-2 related factor 2 (Nrf2), some of which are potentially efficacious clinically. This review will describe the structure and cellular signaling pathways of the NLRP3 inflammasome during ischemic stroke, and current evidence for NLRP3 inflammasome inhibitors.

scholarly journals Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus

2005 ◽  
Vol 201 (6) ◽  
pp. 937-947 ◽  
Author(s):  
Peter A.B. Wark ◽  
Sebastian L. Johnston ◽  
Fabio Bucchieri ◽  
Robert Powell ◽  
Sarah Puddicombe ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Replication ◽  
Cellular Response ◽  
Bronchial Epithelial Cells ◽  
Innate Immune ◽  
Type I ◽  
Interferon Β ◽  
Bronchial Epithelial ◽  
Asthma Exacerbations ◽  
Viral Yield

Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic subjects are more susceptible to these infections. To investigate the underlying mechanisms of this increased susceptibility, we examined virus replication and innate responses to rhinovirus (RV)-16 infection of primary bronchial epithelial cells from asthmatic and healthy control subjects. Viral RNA expression and late virus release into supernatant was increased 50- and 7-fold, respectively in asthmatic cells compared with healthy controls. Virus infection induced late cell lysis in asthmatic cells but not in normal cells. Examination of the early cellular response to infection revealed impairment of virus induced caspase 3/7 activity and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in normal cultures resulted in enhanced viral yield, comparable to that seen in infected asthmatic cultures. Examination of early innate immune responses revealed profound impairment of virus-induced interferon-β mRNA expression in asthmatic cultures and they produced >2.5 times less interferon-β protein. In infected asthmatic cells, exogenous interferon-β induced apoptosis and reduced virus replication, demonstrating a causal link between deficient interferon-β, impaired apoptosis and increased virus replication. These data suggest a novel use for type I interferons in the treatment or prevention of virus-induced asthma exacerbations.

scholarly journals Anti-inflammatory action of type I interferons deduced from mice expressing interferon β

Gene Therapy ◽  
2000 ◽  
Vol 7 (10) ◽  
pp. 817-825 ◽  
Author(s):  
L Boscá ◽  
O G Bodelón ◽  
S Hortelano ◽  
A Casellas ◽  
F Bosch
Keyword(s):  
Type I Interferons ◽  
Type I ◽  
Interferon Β ◽  
Anti Inflammatory ◽  
Inflammatory Action

scholarly journals TBK1, a central kinase in innate immune sensing of nucleic acids and beyond

2020 ◽  
Vol 52 (7) ◽  
pp. 757-767 ◽  
Author(s):  
Ruyuan Zhou ◽  
Qian Zhang ◽  
Pinglong Xu
Keyword(s):  
Nucleic Acids ◽  
Cell Biology ◽  
Innate Immune ◽  
Type I ◽  
Interferon Stimulated Genes ◽  
Immune Sensing ◽  
Mitochondrial Antiviral Signaling ◽  
I Kappa B Kinase ◽  
Innate Immune Sensing ◽  
Mitochondrial Antiviral Signaling Protein

Abstract Sensing of intracellular and extracellular environments is one of the fundamental processes of cell. Surveillance of aberrant nucleic acids, derived either from invading pathogens or damaged organelle, is conducted by pattern recognition receptors (PRRs) including RIG-I-like receptors, cyclic GMP-AMP synthase, absent in melanoma 2, and a few members of toll-like receptors. TANK-binding kinase 1 (TBK1), along with its close analogue I-kappa-B kinase epsilon, is a central kinase in innate adaptor complexes linking activation of PRRs to mobilization of transcriptional factors that transcribe proinflammatory cytokines, type I interferon (IFN-α/β), and myriads interferon stimulated genes. However, it still remains elusive for the precise mechanisms of activation and execution of TBK1 in signaling platforms formed by innate adaptors mitochondrial antiviral signaling protein (MAVS), stimulator of interferon genes protein (STING), and TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as its complex regulations. An atlas of TBK1 substrates is in constant expanding, setting TBK1 as a key node of signaling network and a dominant player in contexts of cell biology, animal models, and human diseases. Here, we review recent advancements of activation, regulations, and functions of TBK1 under these physiological and pathological contexts.

scholarly journals Activation of 2',5'-oligoadenylate synthetase activity on induction of HL-60 leukemia cell differentiation.

1989 ◽  
Vol 9 (9) ◽  
pp. 3897-3903 ◽  
Author(s):  
E L Schwartz ◽  
L A Nilson
Keyword(s):  
Leukemia Cell ◽  
Fold Increase ◽  
Polyclonal Antiserum ◽  
Synthetase Activity ◽  
Human Leukemia ◽  
Type I ◽  
Mrna Levels ◽  
Oligoadenylate Synthetase ◽  
Granulocytic Differentiation ◽  
Ifn Alpha

A 27-fold increase in 2',5'-oligoadenylate synthetase activity, an enzyme associated with the antiproliferative actions of interferon (IFN), was observed after treatment of HL-60 human leukemia cells with dimethyl sulfoxide (DMSO), an inducer of granulocytic differentiation of the cells. Enzyme activity was elevated after 24 h of exposure to DMSO, was maximal at 48 hours, and declined thereafter. A comparable increase was observed after treatment with 1 U of alpha interferon (IFN-alpha) per ml or 8 U of beta interferon (IFN-beta) per ml. Elevated levels of expression of other IFN-inducible genes, including type I histocompatibility antigen (HLA-B) mRNA and 2',5'-oligoadenylate phosphodiesterase activity, were also observed with DMSO treatment. DMSO-treated HL-60 cells had an increased amount of a 1.8-kilobase mRNA for oligoadenylate [oligo(A)] synthetase when compared with that of control cells; both DMSO- and IFN-treated HL-60 cells also expressed 1.6-, 3.4-, and 4.3-kilobase mRNA. The increase in both oligo(A) synthetase activity and mRNA levels was inhibited by polyclonal antiserum to human IFN-alpha; however, no IFN-alpha mRNA could be detected in the cells. Antiserum to IFN-beta or gamma interferon (IFN-gamma) had no effect on oligo(A) synthetase expression or activity nor was there any detectable IFN-beta 1 or IFN-beta 2 mRNA in the cells. The anti-IFN-alpha serum did not block the elevation of HLA-B mRNA in DMSO-treated cells. These observations suggest that the increased expression of oligo(A) synthetase in DMSO-treated cells may be mediated by the release of an IFN-alpha-like factor; however, the levels of any IFN-alpha mRNA produced in the cells were extremely low.

Gene expression analysis of interferon-β treatment in multiple sclerosis

2008 ◽  
Vol 14 (5) ◽  
pp. 615-621 ◽  
Author(s):  
F Sellebjerg ◽  
P Datta ◽  
J Larsen ◽  
K Rieneck ◽  
I Alsing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
T Cell Activation ◽  
Dna Microarrays ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
De Novo ◽  
Type I ◽  
Interferon Β ◽  
Study Gene Expression

Treatment with interferon-β (IFN-β) induces the expression of hundreds of genes in blood mononuclear cells, and the expression of several genes has been proposed as a marker of the effect of treatment with IFN-β. However, to date no molecules have been identified that are stably induced by treatment with IFN-β. We use DNA microarrays to study gene expression in 10 multiple sclerosis (MS) patients who began de novo treatment with IFN-β. After the first injection of IFN-β, the expression of 74 out of 3428 genes changed at least two-fold and statistically significantly (after Bonferroni correction). In contrast, we observed no persisting effects of IFN-β on gene expression. Among the most strongly induced genes was MXA, which has been used in previous biomarker studies in MS. In addition, the study identified the induction of LGALS9 and TCIR1G, involved in negative regulation of T helper type I immunity and T-cell activation, as novel effects of IFN-β therapy in MS.

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