Long Non-Coding RNAs in Sjögren's Disease Pastva, Ondřej; Klein, Kerstin
International journal of molecular sciences,
05/2024, Letnik:
25, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of ...the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers.
Objective
To investigate the role of autophagy in the regulation of cell death in rheumatoid arthritis synovial fibroblasts (RASFs).
Methods
RASFs and osteoarthritis synovial fibroblasts (OASFs) were ...treated with thapsigargin (TG), an inducer of endoplasmic reticulum (ER) stress, and MG132, a proteasome inhibitor. Then, 3‐methyladenine was used as an autophagy inhibitor and bafilomycin A1 as a lysosome inhibitor. Polyubiquitinated proteins, p62, and autophagy induction were evaluated by immunoblotting, immunofluorescence microscopy, and immunohistochemistry, respectively. OASFs were transfected with small interfering RNA targeting autophagy‐linked FYVE protein (ALFY). Cell death was evaluated by flow cytometry and a caspase 3 activity assay.
Results
In RASFs, the induction of autophagy by TG and MG132 was increased compared to that in OASFs. Whereas autophagy promoted a caspase 3–independent induction of cell death under ER stress, autophagy had a protective role in apoptosis induced by proteasome inhibition. Treatment of RASFs with 3‐methyladenine blocked TG‐induced cell death. ER stress induced a strong accumulation of p62‐positive polyubiquitinated protein aggregates, accompanied by the formation of large vacuoles in RASFs but not OASFs. Furthermore, TG‐induced p62 protein expression was increased, whereas TG‐induced ALFY expression was reduced, in RASFs compared to OASFs. ALFY knockdown promoted the accumulation of p62, the formation of polyubiquitinated protein aggregates, and cell death.
Conclusion
Our data provide the first evidence of a dual role of autophagy in the regulation of death pathways in RASFs. A reduced expression of ALFY and the formation of p62‐positive polyubiquitinated protein aggregates promote cell death in RASFs under severe ER stress.
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular ...and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
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•Synovial fibroblasts mediate tissue priming after repeated inflammatory challenge•Tissue priming depends on intracellular complement C3 and C3a receptor expression•Intracellular C3 and C3a receptor drive metabolic reprogramming of fibroblasts•A metabolic shift promotes inflammasome activation and protects from cell senescence
Inflammatory diseases typically involve recurrence and progressive worsening at specific predilection sites, but the underlying mechanisms remain unclear. Friščić et al. reveal that at the center of this inflammatory tissue priming are fibroblasts, which undergo metabolic reprogramming and a shift to a pro-inflammatory state including inflammasome activation.
Despite a long history of assisted reproductive technologies including the use of IVF and artificial insemination, sperm donation has always been a difficult topic in China due to a number of ...political and sociocultural factors. The article will look at the cultural biases against sperm donation, that in the past have led to a severe shortage of sperm donors across the country’s provincial sperm banks. It will also look at the political and regulatory context of sperm donation, and it will explore new developments more recently that have transformed the perception of sperm donation and the attitudes among Chinese men to become sperm donors. In particular, it will look at the media controversy about sperm donation that followed the death of a sperm donor in Wuhan city in 2011, which served as an important catalyst to initiate wider public debate about sperm donation in the media. As the Chinese government is actively seeking to encourage more men to become sperm donors, and media organizations have taken a more active role in collecting, disseminating and transmitting information, this has changed the perception on sperm donation, at least to some degree. Today, there is a more knowledgeable and better informed (male) public, in particular among university students, who is more willing to become sperm donors than it was the case only five years ago. However, as much as this has changed, the end of China’s one-child policy in 2016 has put new pressures on an already strained system of supply and demand of donor sperm in the context of assisted reproductive technologies, as today even more couples are seeking to fulfill their reproductive wishes to also have a second child.
A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts ...from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.
Using the pitching research template elaborated by Faff (2017) as basis, this paper discusses the reverse engineering process on the article "Behavioural effects of nonconscious mimicry and social ...intentions" by Wong, Hartley and Tombs (2017). The main objective is to reflect on the reverse engineering exercise while including major findings of the paper itemized. This paper adds an additional angle on the reverse engineering process, the pitching research template and Robert Faff s efforts in creating a comprehensive research base.
To investigate the effects of BET bromodomain protein inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts (RASF).
The expression of the BET ...bromodomain proteins BRD2, BRD3 and BRD4 was analysed in synovial tissue by immunohistochemistry. RASF were stimulated with tumour necrosis factor (TNF)-α, interleukin (IL)-1β and toll-like receptor (TLR) ligands (Pam3, pIC and lipopolysaccharide (LPS)) in the presence or absence of the BET inhibitor I-BET151, or siRNA targeting BRD2, BRD3 and BRD4. RASF expression of inflammatory mediators, including MMP1, MMP3, IL-6 and IL-8, was measured by q-PCR, q-PCR array and ELISA. Cellular viability, apoptosis, proliferation and chemoattractive properties of RASF were investigated using MTT, cell apoptosis ELISA, BrdU-based proliferation and transwell migration assays.
BRD2, BRD3 and BRD4 proteins were detected in rheumatoid arthritis (RA) synovial tissue, expressed in both RASF and macrophages. I-BET151 suppressed cytokine and TLR ligand-induced secretion of MMP1, MMP3, IL-6 and IL-8, and mRNA expression of more than 70% of genes induced by TNF-α and IL-1β. Combined silencing of BRD2, BRD3 and BRD4 significantly reduced cytokine and TLR ligand-induced expression of a subset of gene products targeted by I-BET151, including MMP1, CXCL10 and CXCL11. I-BET151 treatment of RASF reduced RASF proliferation, and the chemotactic potential for peripheral blood leucocytes of RASF conditioned medium.
Inhibition of BET family proteins suppresses the inflammatory, matrix-degrading, proliferative and chemoattractive properties of RASF and suggests a therapeutic potential in the targeting of epigenetic reader proteins in RA.
Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic inflammation of the joints with severe pain and swelling, joint damage and disability, which leads to joint destruction ...and loss of function. Despite extensive research efforts, the underlying cause for RA is still unknown and current therapies are more or less effective in controlling symptoms but still fail to cure the disease. In recent years, epigenetic modifications were found to strongly contribute to the development of RA by affecting diverse aspects of the disease and modifying gene expression levels and behavior of several cell types, first and foremost joint resident synovial fibroblasts (SF). RASF are the most common cell type at the site of invasion. Owing to their aggressive, intrinsically activated phenotype, RASF are active contributors in joint damage. RASF are characterized by their ability to secrete cytokines, chemokines and joint-damaging enzymes. Furthermore, these cells are resistant to apoptosis, leading to hyperplasia of the synovium. In addition, RASF have invasive and migratory properties that could lead to spreading of the disease to unaffected joints. Epigenetic modifications, including DNA methylation and post-translational histone modifications, such as histone (de)acetylation, histone methylation and histone sumoylation were identified as regulatory mechanisms in controlling aggressive cell activation in vitro and in disease outcome in animal models in vivo. In the last 5 years, the field of epigenetics in RA has impressively increased. In this review we consider the role of diverse epigenetic modifications in the development of RA, with a special focus on epigenetic modifications in RASF.
Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has ...excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.
We identify putative causal variants, enhancers, genes, and cell types for 30-60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.
Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.
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