scholarly journals Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 785
Author(s):  
Alessandra Tesser ◽  
Giulia Maria Piperno ◽  
Alessia Pin ◽  
Elisa Piscianz ◽  
Valentina Boz ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Lupus Erythematosus ◽  
Bacterial Infections ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptor ◽  
Systemic Lupus ◽  
Toll Like Receptor 4 ◽  
Murine Bone Marrow ◽  
Cellular Models

Cytoplasmic nucleic acids sensing through cGAS-STING-TBK1 pathway is crucial for the production of antiviral interferons (IFNs). IFN production can also be induced by lipopolysaccharide (LPS) stimulation through Toll-like receptor 4 (TLR4) in appropriate conditions. Of note, both IFN production and dysregulated LPS-response could play a role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Indeed, LPS can trigger SLE in lupus-prone mice and bacterial infections can induce disease flares in human SLE. However, the interactions between cGAS and TLR4 pathways to IFNs have been poorly investigated. To address this issue, we studied LPS-stimulation in cellular models with a primed cGAS-STING-TBK1 pathway. cGAS-stimulation was naturally sustained by undigested self-nucleic acids in fibroblasts from DNase2-deficiency interferonopathy, whilst it was pharmacologically obtained by cGAMP-stimulation in THP1 cells and murine bone marrow-derived dendritic cells. We showed that cells with a primed cGAS-STING-TBK1 pathway displayed enhanced IFNs production after TLR4-challenge. STING-inhibition did not affect IFN production after LPS alone, but prevented the amplified IFN production in cGAMP-primed cells, suggesting that functional STING is required for priming-dependent enhancement. Furthermore, we speculated that an increased PIK3AP1 expression in DNase2-deficient fibroblasts may link cGAMP-priming with increased LPS-induced IFN production. We showed that both the hyper-expression of PIK3API and the enhanced LPS-induced IFN production can be contrasted by STING inhibitors. Our results may explain how bacterial LPS can synergize with cGAS-pathway in promoting the development of SLE-like autoimmunity.

scholarly journals Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

2018 ◽  
Vol 25 (24) ◽  
pp. 2797-2810 ◽  
Author(s):  
Elisa Piscianz ◽  
Eva Cuzzoni ◽  
Rajan Sharma ◽  
Alessandra Tesser ◽  
Pooja Sapra ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Nucleic Acids ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
18Th Century ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Microbial Dna ◽  
Type I Interferonopathies

The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. <p> Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGASSTING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. <p> This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. <p> We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

Type I Interferons in Autoimmune Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 369-393 ◽  
Author(s):  
Mary K. Crow ◽  
Mikhail Olferiev ◽  
Kyriakos A. Kirou
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Pathway Activation ◽  
Interferon Pathway ◽  
Chronic Activation

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

scholarly journals VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus

Immunology ◽  
2014 ◽  
Vol 142 (4) ◽  
pp. 594-602 ◽  
Author(s):  
Paolo Fagone ◽  
Karuppiah Muthumani ◽  
Katia Mangano ◽  
Gaetano Magro ◽  
Pier Luigi Meroni ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Murine Model ◽  
Lupus Erythematosus ◽  
Toll Like Receptor ◽  
Systemic Lupus ◽  
Toll Like Receptor 4

scholarly journals Interferon score is increased in incomplete systemic lupus erythematosus and correlates with myxovirus-resistance protein A in blood and skin

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Wietske M. Lambers ◽  
Karina de Leeuw ◽  
Berber Doornbos-van der Meer ◽  
Gilles F.H. Diercks ◽  
Hendrika Bootsma ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Protein A ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Skin Symptoms ◽  
Skin Biopsies ◽  
Resistance Protein ◽  
Unaffected Skin

Abstract Objectives Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Methods Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. Results IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). Conclusions IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.

Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on Epidemiology, Risk Factors and Prevention

2020 ◽  
Vol 18 (6) ◽  
pp. 549-565 ◽  
Author(s):  
Myrto Kostopoulou ◽  
Dionysis Nikolopoulos ◽  
Ioannis Parodis ◽  
George Bertsias
Keyword(s):  
Risk Factors ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Statin Treatment ◽  
Type I Interferons ◽  
Type I ◽  
Lifestyle Modifications ◽  
Systemic Lupus ◽  
Increased Risk ◽  
Atherogenic Dyslipidaemia

Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.

scholarly journals Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37000 ◽  
Author(s):  
Emily C. Somers ◽  
Wenpu Zhao ◽  
Emily E. Lewis ◽  
Lu Wang ◽  
Jeffrey J. Wing ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus
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