JAK Inhibitors Suppress Innate Epigenetic Reprogramming: a Promise for Patients with Sjögren’s Syndrome

Charras, Amandine; Arvaniti, Pinelopi; Dantec, Christelle Le; Arleevskaya, Marina I; Zachou, K.; Dalekos, George Ν.; Bordon, Anne; Renaudineau, Yves

doi:10.1007/s12016-019-08743-y

Cited by 43 publications

(37 citation statements)

References 54 publications

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“…JAK-STAT signaling represents such a survival pathway involved in stemness, the epithelial-mesenchymal transition, and cancerogenesis (Deschenes-Simard et al, 2019; Ganguly et al, 2018; Jin et al, 2016; Lin et al, 2020; Lu et al, 2019). STAT3 in particular has been shown to fine-tune type I IFN responses (Charras et al, 2020; Tsai et al, 2019). This appears to be important to ensure proper development, because type I IFN signaling impairs stem cell function and the potential for differentiation (Eggenberger et al, 2019; Yu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

DDI2 protease activity controls embryonic development and inflammation via TCF11/NRF1

Sivá

Procházková

Procházka

et al. 2020

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DDI2 is an aspartic protease that cleaves polyubiquitinated substrates. Upon proteotoxic stress, DDI2 activates the ER-bound transcription factor TCF11/NRF1 (NFE2L1), a master regulator of proteostasis maintenance in mammalian cells, and ensures the expression of rescue factors including proteasome subunits. Here we describe the consequences of DDI2 ablation both in vivo and in cells. Knock-out of DDI2 in mice resulted in embryonic lethality at E12.5 with severe developmental failure. Molecular characterization of the embryos and surrogate DDI2 knock-out cell lines showed insufficient proteasome expression with proteotoxic stress, accumulation of high molecular weight ubiquitin conjugates, and induction of the unfolded protein and integrated stress responses. We also show that DDI2 KO-induced proteotoxic stress causes the cell-autonomous innate immune system to induce a type I interferon signature. These results indicate an important role for DDI2 in the proteostasis network of cells and tissues and in the maintenance of a balanced immune response.

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Section: Discussionmentioning

confidence: 99%

DDI2 protease activity controls embryonic development and inflammation via TCF11/NRF1

Sivá

Procházková

Procházka

et al. 2020

Preprint

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“…Based on the hypothesis mentioned above and our recent study showing an interplay between ROS and the JAK/STAT pathway to control epigenetic actors (35), the aim of our study was to investigate the role of ROS on the expression of ICAM-1 and PD-L1, as well as to elucidate the potential reversible effect of JAK inhibitors and NAC in this process, a finding that could lead to the development of a novel therapeutic target in this still incurable disease.…”

Section: Introductionmentioning

confidence: 99%

JAK Inhibitors and Oxidative Stress Control

et al. 2019

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Primary Sjögren's syndrome (SjS) is a complex autoimmune epithelitis, with few treatment options, but the use of Janus kinase (JAK) inhibitors is promising because suppression of the JAK/signal transducer and activator of transcription (STAT) pathway improves sicca manifestations. Playing a primary and pathogenic role in disease development, the oxidative stress response is upregulated in activated salivary gland epithelial cells (SGECs) from patients with SjS. Therefore, the aim of this study was to investigate whether JAK inhibitors would suppress SGEC activation in response to an oxidative stress. For this purpose, the human salivary gland (HSG) cell line was used, and cells were treated with the reactive oxygen species (ROS) inducer hydrogen peroxide (H2O2) or with interferons (IFN Type I and Type II), used as positive controls, to mimic activated SGECs as observed in SjS patients. Afterward, the levels of the intracellular adhesion molecule-1 (ICAM-1) and the regulatory programmed-death ligand-1 (PD-L1) were measured by real-time PCR and flow cytometry, and the STAT1/3 phosphorylation status was assessed by Western blotting. Using the HSG cell line, our results showed that both ICAM-1 and PD-L1 are induced by ROS through pSTAT3, and that this activation pathway is reversed by the use of JAK inhibitors, AG490 and ruxolitinib, as well as by N-acetylcysteine, which is a direct inhibitor of ROS. These findings open new perspectives regarding the pathogenesis and therapeutic possibilities for SjS.

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“…Amplification and detection were performed in a Lightcycler R 96 Instrument (Roche Life Sciences, Bavaria, Germany) under the following conditions: 1 cycle at 50°C for 2min and 95°C for 10min and 40 cycles at 95°C for 15sec and 60°C for 1min. The primers used for DNMT3A, DNMT3B, TET1 and TET2 were as previously described (28) Antigen retrieval was performed in a Tris-EDTA (pH=9) solution at 98°C for 20 min, while endogenous peroxidase activity was blocked by quenching the tissue sections with 3.0% hydrogen peroxide in methanol for 10 minutes. The sections were then washed with 1% donkey serum in PBS-0,4% Triton X-100 (TBST) solution for 5 minutes for permeabilization, followed by incubation with primary antibody (dilution 1/150) in room temperature for 30 minutes.…”

Section: Dnmt1 Dnmt3a Dnmt3b Tet1 Tet2 and Tet3 Mrna Quantificationmentioning

confidence: 99%

Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis

Zachou

Arvaniti

Lyberopoulou

et al. 2021

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Objective: AIH is a chronic liver disease of unknown aetiology with favourable response to immunosuppression. Little is known about the impact of methylation modifications on disease pathogenesis. Design: 10 patients with AIH at diagnosis (time-point 1; tp1), 9 with primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. 8/10 AIH patients were also investigated following biochemical remission (time-point 2; tp2). Peripheral CD19(+)- and CD4(+)-cells were isolated to study global DNA methylation (5mC)/hydroxymethylation (5hmC) by ELISA and mRNA of DNA methylation (DNMT1/3A/3B)/hydroxymethylation enzymes (TET1/2/3) by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+)-cells (Illumina HumanMethylation 850K array) in AIH and HC. Differences in total 5mC/5hmC state between AIH-tp1 and HC were also assessed by immunohistochemistry (IHC) on paraffin embedded liver sections. Results: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+) lymphocytes from AIH-tp1 patients compared to HC and PBC respectively, without affecting global DNA 5mC/5hmC. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (p=0.03). In remission (AIH-tp2), DNMT3A decreased in both CD19(+) and CD4(+)-cells (p=0.02, p=0.03, respectively). EWAS in CD4(+)-cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC confirmed increased 5hmC staining of periportal infiltrating lymphocytes in AIH-tp1. Conclusion: Altered expression of TET1 and DNMT3A, characterizes peripheral immune cells in AIH. DNMT3A is associated with disease activity and decreased following therapeutic response. Gene specific DNA methylation modifications affect immunologic pathways that may play an important role in AIH pathogenesis.

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JAK Inhibitors Suppress Innate Epigenetic Reprogramming: a Promise for Patients with Sjögren’s Syndrome

Cited by 43 publications

References 54 publications

DDI2 protease activity controls embryonic development and inflammation via TCF11/NRF1

DDI2 protease activity controls embryonic development and inflammation via TCF11/NRF1

JAK Inhibitors and Oxidative Stress Control

Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis

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