scholarly journals LncRNAMalat1inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity

2020 ◽  
Vol 117 (38) ◽  
pp. 23695-23706 ◽  
Author(s):  
Wei Liu ◽  
Ziqiao Wang ◽  
Lun Liu ◽  
Zongheng Yang ◽  
Shuo Liu ◽  
...  
Keyword(s):  
Viral Infection ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Negative Regulator ◽  
Type I ◽  
Type I Ifn ◽  
Peripheral Blood Mononuclear ◽  
Interactive Network ◽  
Antiviral Innate Immunity

Long noncoding RNAs (lncRNAs) involved in the regulation of antiviral innate immune responses need to be further identified. By functionally screening the lncRNAs in macrophages, here we identified lncRNAMalat1, abundant in the nucleus but significantly down-regulated after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production.Malat1directly bound to the transactive response DNA-binding protein (TDP43) in the nucleus and prevented activation of TDP43 by blocking the activated caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 increased the nuclear IRF3 protein level by binding and degradingRbck1pre-mRNA to prevent IRF3 proteasomal degradation upon viral infection, thus selectively promoting antiviral IFN-I production. Deficiency ofMalat1enhanced antiviral innate responses in vivo, accompanying the increased IFN-I production and reduced viral burden. Importantly, the reducedMALAT1, augmented IRF3, and increasedIFNAmRNA were found in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. Therefore, the down-regulation ofMALAT1in virus-infected cells or in human cells from autoimmune diseases will increase host resistance against viral infection or lead to autoinflammatory interferonopathies via the increased type I IFN production. Our results demonstrate that the nuclearMalat1suppresses antiviral innate responses by targeting TDP43 activation via RNA-RBP interactive network, adding insight to the molecular regulation of innate responses and autoimmune pathogenesis.

scholarly journals Innate triggering and antiviral effector functions of activin A

2021 ◽  
Author(s):  
Kinda Al-Hourani ◽  
Narayan Ramamurthy ◽  
Emanuele Marchi ◽  
Ruth M Eichinger ◽  
Lian N Lee ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Activin A ◽  
Type I ◽  
Type I Ifn ◽  
Effector Functions

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions, including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

scholarly journals Inhibitory CD200-receptor signaling is rewired by type I interferon

2020 ◽  
Author(s):  
Michiel van der Vlist ◽  
M. Inês Pascoal Ramos ◽  
Lucas L. van den Hoogen ◽  
Sanne Hiddingh ◽  
Laura Timmerman ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Type I ◽  
Type I Ifn ◽  
Peripheral Blood Mononuclear ◽  
Cd200 Receptor ◽  
Inhibitory Function ◽  
Human Mononuclear Cells ◽  
Rps6 Phosphorylation

AbstractCD200 Receptor 1 (CD200R) is an established inhibitory immune receptor that inhibits TLR-induced cytokine production through Dok2 and RasGAP. RasGAP can be cleaved under certain conditions of mild cellular stress. We found that in the presence of cleaved RasGAP, CD200R loses its capacity to inhibit rpS6 phosphorylation. Furthermore, IFNα pre-stimulation of human mononuclear cells results in increased amounts of cleaved RasGAP. Coherently, upon pretreatment with increasing concentrations of IFNα, CD200R gradually shifts from an inhibitor to a potentiator of TLR7/8-induced IFNG mRNA production. In peripheral blood mononuclear cells from Systemic Lupus Erythematosus (SLE) patients, a prototypic type I IFN disease, we found an increased proportion of cleaved RasGAP compared to healthy controls. In line with this, in subsets of SLE patients the inhibitory function of CD200R is lost or converted to a potentiating signal for IFNG mRNA production. Thus, our data show that type I IFN rewires CD200R signaling and suggest that this cell-extrinsic regulation of signaling could contribute to perpetuation of inflammation in SLE.

scholarly journals Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3435-3442 ◽  
Author(s):  
Arman Aue ◽  
Franziska Szelinski ◽  
Sarah Y Weißenberg ◽  
Annika Wiedemann ◽  
Thomas Rose ◽  
...  
Keyword(s):  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Mononuclear Cells ◽  
Janus Kinase ◽  
T Cell Subsets ◽  
Type I ◽  
Type I Ifn ◽  
Peripheral Blood Mononuclear ◽  
B Cell Subsets

Abstract Objectives SLE is characterized by two pathogenic key signatures, type I IFN and B-cell abnormalities. How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT). JAK-STAT inhibition is an attractive therapeutic possibility for SLE. We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared with other autoimmune diseases and healthy controls (HD) and related it to disease activity. Methods Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T cells of 21 HD, 10 rheumatoid arthritis (RA), seven primary Sjögren’s (pSS) and 22 SLE patients was analysed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs (peripheral blood mononuclear cells) of SLE patients and HD after IFNα and IFNγ incubation were further investigated. Results SLE patients showed substantially higher STAT1 but not pSTAT1 in B- and T-cell subsets. Increased STAT1 expression in B-cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker. STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ. Conclusion Enhanced expression of STAT1 by B-cell candidates as a key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold a promise to block STAT1 expression and control plasmablast induction in SLE.

scholarly journals Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Stimulated by Mycobacterium tuberculosis PPE57 Identifies Characteristic Genes Associated With Type I Interferon Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Fanli Yi ◽  
Jing Hu ◽  
Xiaoyan Zhu ◽  
Yue Wang ◽  
Qiuju Yu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glutamic Acid ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Proline-glutamic acid (PE)- and proline-proline-glutamic acid (PPE)-containing proteins are exclusive to Mycobacterium tuberculosis (MTB), the leading cause of tuberculosis (TB). In this study, we performed global transcriptome sequencing (RNA-Seq) on PPE57-stimulated peripheral blood mononuclear cells (PBMCs) and control samples to quantitatively measure the expression level of key transcripts of interest. A total of 1367 differentially expressed genes (DEGs) were observed in response to a 6 h exposure to PPE57, with 685 being up-regulated and 682 down-regulated. Immune-related gene functions and pathways associated with these genes were evaluated, revealing that the type I IFN signaling pathway was the most significantly enriched pathway in our RNA-seq dataset, with 14 DEGs identified therein including ISG15, MX2, IRF9, IFIT3, IFIT2, OAS3, IFIT1, IFI6, OAS2, OASL, RSAD2, OAS1, IRF7, and MX1. These PPE57-related transcriptomic profiles have implications for a better understanding of host global immune mechanisms underlying MTB infection outcomes. However, more studies regarding these DEGs and type I IFN signaling in this infectious context are necessary to more fully clarify the underlying mechanisms that arise in response to PPE57 during MTB infection.

scholarly journals Cross-Disease Innate Gene Signature: Emerging Diversity and Abundance in RA Comparing to SLE and SSc

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Anna Petrackova ◽  
Pavel Horak ◽  
Martin Radvansky ◽  
Martina Skacelova ◽  
Regina Fillerova ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Association Rule ◽  
Mononuclear Cells ◽  
Gene Signature ◽  
Type I ◽  
Limited Data ◽  
Peripheral Blood Mononuclear ◽  
Expression Of Genes ◽  
Rule Analysis ◽  
Disease Study

Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n=36, DAS28≥3.2), SLE (n=28, SLEDAI>6), and SSc (n=22, revised EUSTAR index>2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (Pcorr<0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (Pcorr<0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.

The Role of the Tissue Factor Pathway in the Hypercoagulable State in Patients with the Antiphospholipid Syndrome

1998 ◽  
Vol 79 (02) ◽  
pp. 276-281 ◽  
Author(s):  
Olga Amengual ◽  
Tatsuya Atsumi ◽  
Graham Hughes ◽  
Munther Khamashta
Keyword(s):  
Tissue Factor ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Umbilical Vein ◽  
Antigen Expression ◽  
Peripheral Blood Mononuclear ◽  
Tissue Factor Pathway

SummaryThe antiphospholipid syndrome (APS) is characterised by both arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopaenia in association with antiphospholipid antibodies (aPL). To explore further the pathogenesis of thrombosis in APS, we evaluated the behaviour of tissue factor (TF) pathway in patients with APS. Plasma antigen levels of soluble TF and tissue factor pathway inhibitor (TFPI), a physiological regulator of TF dependent coagulation activation, were measured in 57 APS patients (36 primary and 21 secondary to systemic lupus erythematosus). Significantly elevated levels of both TF and TFPI were found in APS patients compared with 25 healthy controls (279 ± 15 vs. 217 ± 17 pg/ml, p = 0.01; 56.24 ± 2.00 vs. 47.92 ± 2.22 ng/ml, p = 0.01, respectively), suggesting in vivo upregulation of TF pathway in patients with APS. By flow-cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of APS plasmas than in control plasmas (24.23 ± 3.11 vs. 12.78 ± 1.57%, p = 0.002). Peripheral blood mononuclear cells (PBMC) also expressed more procoagulant activity (PCA) when incubated in the presence of APS plasmas than in control plasmas (1.80 ± 0.12 vs. 1.35 ± 0.054, p = 0.001) implying that TF up-regulation in APS was reproducible in vitro. Human monoclonal anticardiolipin antibodies induced PCA on PBMC and also TF mRNA on both PBMC and human umbilical vein endothelial cells shown by reverse-transcription polymerase chain reaction. These data strongly suggest that the TF pathway is implicated in the pathogenesis of aPL related thrombosis.

scholarly journals Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome

2016 ◽  
Vol 76 (2) ◽  
pp. 450-457 ◽  
Author(s):  
Robert C Grenn ◽  
Srilakshmi Yalavarthi ◽  
Alex A Gandhi ◽  
Nayef M Kazzaz ◽  
Carlos Núñez-Álvarez ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Type I Interferons ◽  
Functional Assay ◽  
Type I ◽  
Primary Antiphospholipid Syndrome ◽  
Type I Ifn ◽  
Endothelial Progenitor ◽  
Endothelial Progenitors

ObjectivesPatients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS.MethodsWe studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes.ResultsEndothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody.ConclusionsWe describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

scholarly journals The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

2021 ◽  
Vol 17 (4) ◽  
pp. e1009530
Author(s):  
Jian Xu ◽  
Yunhong Cai ◽  
ZhenBang Ma ◽  
Bo Jiang ◽  
Wenxiao Liu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Nuclear Export ◽  
Rna Virus ◽  
Negative Regulator ◽  
Innate Response ◽  
Viral Propagation ◽  
Dead Box ◽  
Antiviral Innate Immunity

Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3–METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.

scholarly journals Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

2018 ◽  
Vol 77 (11) ◽  
pp. 1653-1664 ◽  
Author(s):  
Mrinal K Sarkar ◽  
Grace A Hile ◽  
Lam C Tsoi ◽  
Xianying Xing ◽  
Jianhua Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lupus Erythematosus ◽  
Cutaneous Lupus Erythematosus ◽  
Ultraviolet B ◽  
Immunofluorescent Staining ◽  
Tunel Staining ◽  
Type I ◽  
Type I Ifn ◽  
Cutaneous Lupus

ObjectiveSkin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin.MethodsmRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin.ResultsIFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10−04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis.ConclusionCollectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

scholarly journals Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero

RMD Open ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. e000989 ◽  
Author(s):  
Malin Hedlund ◽  
Gudny Ella Thorlacius ◽  
Margarita Ivanchenko ◽  
Vijole Ottosson ◽  
Nikolaos Kyriakidis ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
In Utero ◽  
Type I ◽  
Type I Ifn ◽  
Immunomodulatory Treatment ◽  
Peripheral Blood Mononuclear ◽  
Cellular Activation ◽  
Sialic Acid Binding ◽  
Healthy Control ◽  
System Activation

ObjectiveIn utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment.MethodsBlood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays.ResultsWe observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma.ConclusionsRo/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.

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