Targeting mitochondrial double-stranded RNAs ameliorates autoimmune characteristics of Sjӧgren’s syndrome

AbstractSjӧgren’s syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating type I IFN response in SS. We find that mt-dsRNAs are elevated in the saliva and tear of SS patients and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house- developed 3D culture, we show that dsRNA stimulation increases mt-dsRNAs expression via JAK1/STAT pathway and facilitates their cytosolic export, which is accompanied by autoimmune signatures observed in SS. We further show that muscarinic receptor ligand acetylcholine or antioxidant resveratrol ameliorates autoimmune characteristics by preventing mt-dsRNA- mediated immune activation. In addition, direct suppression of mt-dsRNAs reverses the autoimmune signatures of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation and suggests mt-dsRNAs as an important key to the puzzle of SS.SummaryMitochondrial double-stranded RNA levels are elevated in the tear and saliva of SS patients. These RNAs promote type I interferon signature, as well as other autoimmune phenotypes in SS. Downregulation of mitochondrial dsRNAs alleviates autoimmune signatures of SS in salivary gland epithelial cells.Graphical Abstractmt-dsRNAs as the molecular mediator of autoimmune phenotypes in SS.mt-dsRNAs are elevated in both human samples and mouse model of SS and function to exacerbate dsRNA-induced autoimmune phenotypes in SS. Countering the accumulation of mt- dsRNAs alleviates the autoimmune phenotypes in SGECs.

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The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/706825 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 26

Author(s):

Isaac T. W. Harley ◽

Timothy B. Niewold ◽

Rebecca M. Stormont ◽

Kenneth M. Kaufman ◽

Stuart B. Glenn ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Systemic Autoimmune Disease ◽

Type I ◽

Nucleotide Polymorphisms ◽

Type I Ifn ◽

Systemic Lupus ◽

Genome Wide

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated theIFNKlocus in SLE susceptibility. We studiedIFNKsingle nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93,P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific.IFNKSNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association betweenIFNKSNPs and SLE and skin phenotypes. The serum IFN association suggests thatIFNKvariants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

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Poly (I:C) downregulates platelet production and function through type I interferon

Thrombosis and Haemostasis ◽

10.1160/th14-11-0951 ◽

2015 ◽

Vol 114 (11) ◽

pp. 982-993 ◽

Cited By ~ 11

Author(s):

Leonardo Rivadeneyra ◽

Roberto Gabriel Pozner ◽

Roberto Meiss ◽

Carlos Fondevila ◽

Ricardo Martin Gómez ◽

...

Keyword(s):

Bone Marrow ◽

Viral Infections ◽

Type I Interferons ◽

Poly I:C ◽

Synthetic Analogue ◽

Type I ◽

Platelet Production ◽

Underlying Mechanisms ◽

And Function

SummaryThrombocytopenia is a frequent complication of viral infections; the underlying mechanisms appear to depend on the identity of the virus involved. Previous research, including reports from our group, indicates that as well as having antiviral activity type I interferons (IFN I) selectively downregulate platelet production. In this study we extended understanding of the role of endogenous IFN I in megakaryo/ thrombopoiesis by evaluating platelet and megakaryocyte physiology in mice treated with polyinosinic:polycytidylic acid [poly (I:C)], a synthetic analogue of double-stranded RNA, Toll-like receptor-3 ligand and strong IFNp inducer. Mice-treated with poly (I:C) showed thrombocytopaenia, an increase in mean platelet volume and abnormal haemostatic and inflammatory platelet-mediated functionality, indicated by decreased fibrinogen binding and platelet adhesion, prolonged tail bleeding times and impaired P-Selectin externalisation, RANTES release and thrombin-induced platelet-neutrophil aggregate formation. These changes were associated with an increase in size and an abnormal distribution of bone marrow megakaryocytes within the vascular niche and were directly correlated with the plasmatic and bone marrow IFNp levels. All these effects were absent in genetically modified mice lacking the IFN I receptor. Our results suggest that IFN I is the central mediator of poly (I:C)-induced thrombocytopenia and platelet dysfunction and indicate that these abnormalities are due to changes in the last stages of megakaryocyte development. These data provide new evidence for the role of IFN I in megakaryocyte distribution in the bone marrow niches and its influence on thrombopoiesis and haemostasis.

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Type I Interferons promote maintenance and function of follicular T helper cells in vitro

10.1055/s-0038-1677255 ◽

2019 ◽

Author(s):

S Ehrlich ◽

K Wild ◽

M Smits ◽

K Zoldan ◽

M Hofmann ◽

...

Keyword(s):

T Helper Cells ◽

Type I Interferons ◽

Type I ◽

T Helper ◽

Helper Cells ◽

Follicular T Helper Cells ◽

And Function

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The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria

Current Immunology Reviews ◽

10.2174/157339509788166994 ◽

2009 ◽

Vol 5 (2) ◽

pp. 143-149

Author(s):

Marja Ojaniemi ◽

Mari Liljeroos ◽

Reetta Vuolteenaho

Keyword(s):

Type I Interferons ◽

Host Responses ◽

Type I ◽

Toll Like Receptors

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POS0611 THE EFFECT OF RITUXIMAB BIOSIMILAR THERAPY ON THE EXPRESSION OF INTERFERON-STIMULATED GENES (“INTERFERON SIGNATURE”) IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1551 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 542.2-542

Author(s):

A. Avdeeva ◽

E. Tchetina ◽

G. Markova ◽

E. Nasonov

Keyword(s):

Rheumatoid Arthritis ◽

Gene Signature ◽

Response To Therapy ◽

Type I Interferons ◽

Control Group ◽

Type I ◽

Acute Phase Reactants ◽

Interferon Signature ◽

Interferon Stimulated Genes ◽

Healthy Donors

Background:Type I interferons (IFN-Is) are a group of molecules with pleiotropic effects on the immune system forming a crucial link between innate and adaptive immune responses. The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including rheumatoid arthritis. IFN activity is usually quantified using expression of interferon-stimulated genes (ISGs) referred to as an IFN signature. Acellbia (BIOCAD) is the first Russian rituximab (RTX) biosimilar which was approved for medical use in rheumatoid arthritis (RA) patients in Russia and some CIS countries.Objectives:To evaluate the changes in expression of ISGs in patients (pts) with RA during RTX biosimilar therapyMethods:20 RA pts (18 woman, Me;IQR age 61.5(54-66.5) years, disease duration 39.5(20-84) months, mean DAS 28 5.6(4.9-6.8)) received two intravenous RTX biosimilar infusions (600 mg №2) in combination with DMARDs and glucocorticoids. Laboratory biomarkers were assessed at baseline and 24 weeks after the first infusion of RTX. 5 genes (IFI44L, MX1, IFIT 1, RSAD2, EPSTI1) were selected for evaluation of the “interferon signature” (Type I IFN gene signature – IFNGS). IFI44L and IFIT1 expression was undetectable, therefore the remaining three genes (MSX1, EPSTI1, RSAD2) were included into further analysis. IFNGS was calculated as the average expression values of the three selected genes. The control group included 20 age and gender matching healthy donors.Results:The baseline expression levels of MX1-11.48 (5.45-19.38), EPSTI1-12.83 (5.62-19.64), RSAD2-5.16 (2.73-10.4), and IFNGS-10.3 (5.18-17.12) in RA patients were significantly higher compared to healthy donors– 1,26 (0,73-1,6); 1,06 (0,81-1,48); 0,93 (0,72-1,19); 1,09 (0,92-1,42), (p<0.05, respectively). IFNGS was detected in 15 (75%) patients, and was not found in 5 (15%) patients. RTX induced reduction in disease activity, and the level of acute phase reactants (ESR, CRP) after 12 and 24 weeks of therapy, p<0.05 (fig.1). Increased RSAD 2 expression (p<0.05) and a trend to increasing IFNGS levels (p=0.06) were documented in the whole group, and also in patients with moderate treatment effects by week 24. Among patients with a good EULAR response to therapy, changes in expression were not significant (p> 0.05) (fig.1)Figure 1.Conclusion:Expression of IFN-stimulated genes was increased in RA patients compared to healthy donors. Increased RSAD2 and IFNGS expression was documented in patients with moderate effect of RTX therapy, therefore, these findings have important clinical relevance as predictors of RA clinical course which necessitates personified approach to treatment.Disclosure of Interests:None declared

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Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽

10.3390/pathogens10060675 ◽

2021 ◽

Vol 10 (6) ◽

pp. 675

Author(s):

Samira Elmanfi ◽

Mustafa Yilmaz ◽

Wilson W. S. Ong ◽

Kofi S. Yeboah ◽

Herman O. Sintim ◽

...

Keyword(s):

Immune Response ◽

Periodontal Disease ◽

Innate Immune ◽

Host Cells ◽

Type I Interferons ◽

Type I ◽

Vaccine Adjuvants ◽

Cyclic Dinucleotides ◽

Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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