TNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis.
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ABSTRACT:
SUBMITTER: Xie Z
PROVIDER: S-EPMC8433149 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Apoptotic cell death is essential for development and tissue homeostasis. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptotic cells in living tissue has been elusive. Here, we use a newly developed technique to track apoptotic cells in real time as they emerge and are cleared from the zebrafish brain. We find that apoptotic cells are remarkably motile, frequently migrating several cell diameters to the periphery of living tissues. F-actin remodeling occurs in surrounding cells, but also within the apoptotic cells themselves, suggesting a cell-autonomous component of motility. During the first 2 days of development, engulfment is rare, and most apoptotic cells lyse at the brain periphery. By 3 days postfertilization, most cell corpses are rapidly engulfed by macrophages. This engulfment requires the guanine nucleotide exchange factor elmo1. In elmo1-deficient macrophages, engulfment is rare and may occur through macropinocytosis rather than directed engulfment. These findings suggest that clearance of apoptotic cells in living vertebrates is accomplished by the combined actions of apoptotic cell migration and elmo1-dependent macrophage engulfment.
| S-EPMC3597770 | biostudies-literature
Project description:Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy donors (HDMSCs) using the combination of tumor necrosis factor alpha (TNF-?) and cycloheximide (CHX). We found that ASMSCs treated with TNF-? and CHX showed higher apoptosis levels compared to HDMSCs. During apoptosis, ASMSCs expressed significantly more TRAIL-R2, which activated both the death receptor pathway and mitochondria pathway by increasing the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3. Inhibiting TRAIL-R2 expression using shRNA eliminated the apoptosis differences between HDMSCs and ASMSCs by partially reducing ASMSCs apoptosis but minimally affecting that of HDMSCs. Furthermore, the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3 were comparable between HDMSCs and ASMSCs after TRAIL-R2 inhibition. These results indicated that increased TRAIL-R2 expression results in enhanced ASMSCs apoptosis and may contribute to AS pathogenesis.
| S-EPMC5274669 | biostudies-literature
Project description:Ankylosing spondylitis (AS) is a type of spondyloarthropathies, the diagnosis of which is often delayed. The lack of early diagnosis tools often delays the institution of appropriate therapy. This study aimed to investigate the systemic metabolic shifts associated with AS and TNF inhibitors treatment. Additionally, we aimed to define reliable serum biomarkers for the diagnosis. We employed an untargeted technique, ultra-performance liquid chromatography-mass spectroscopy (LC-MS), to analyze the serum metabolome of 32 AS individuals before and after 24-week TNF inhibitors treatment, as well as 40 health controls (HCs). Multivariate and univariate statistical analyses were used to profile the differential metabolites associated with AS and TNF inhibitors. A diagnostic panel was established with the least absolute shrinkage and selection operator (LASSO). The pathway analysis was also conducted. A total of 55 significantly differential metabolites were detected. We generated a diagnostic panel comprising five metabolites (L-glutamate, arachidonic acid, L-phenylalanine, PC (18:1(9Z)/18:1(9Z)), 1-palmitoylglycerol), capable of distinguishing HCs from AS with a high AUC of 0.998, (95%CI: 0.992-1.000). TNF inhibitors treatment could restore the equilibrium of 21 metabolites. The most involved pathways in AS were amino acid biosynthesis, glycolysis, glutaminolysis, fatty acids biosynthesis and choline metabolism. This study characterized the serum metabolomics signatures of AS and TNF inhibitor therapy. We developed a five-metabolites-based panel serving as a diagnostic tool to separate patients from HCs. This serum metabolomics study yielded new knowledge about the AS pathogenesis and the systemic effects of TNF inhibitors.
| S-EPMC7933516 | biostudies-literature
Project description:We aim to generate an artificial neural network (ANN) model to predict early TNF inhibitor users in patients with ankylosing spondylitis. The baseline demographic and laboratory data of patients who visited Samsung Medical Center rheumatology clinic from Dec. 2003 to Sep. 2018 were analyzed. Patients were divided into two groups: early-TNF and non-early-TNF users. Machine learning models were formulated to predict the early-TNF users using the baseline data. Feature importance analysis was performed to delineate significant baseline characteristics. The numbers of early-TNF and non-early-TNF users were 90 and 505, respectively. The performance of the ANN model, based on the area under curve (AUC) for a receiver operating characteristic curve (ROC) of 0.783, was superior to logistic regression, support vector machine, random forest, and XGBoost models (for an ROC curve of 0.719, 0.699, 0.761, and 0.713, respectively) in predicting early-TNF users. Feature importance analysis revealed CRP and ESR as the top significant baseline characteristics for predicting early-TNF users. Our model displayed superior performance in predicting early-TNF users compared with logistic regression and other machine learning models. Machine learning can be a vital tool in predicting treatment response in various rheumatologic diseases.
| S-EPMC7679386 | biostudies-literature
Project description:ObjectiveGut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria.MethodsFecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis.ResultsSignificantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity.ConclusionsMicrobiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.
| S-EPMC9351697 | biostudies-literature
Project description:ObjectivesAnkylosing spondylitis (AS) is challenging to diagnose in its early stages, and treatment options are limited.MethodsGEO2R analysis and weighted gene co-expression network analysis (WGCNA) were used to identify DEGs and key modules. Kyoto Encyclopedia of Genes and Genomes analysis and Protein-protein interactions were used to identify core genes. Receiver operating characteristic curve, chi-square and t-test were used to analyze the correlation between gene expression and clinicopathological characteristics. Gene expression was detected using Real-time polymerase chain reaction and western blotting.ResultsGEO2R analysis and WGCNA identified 1100 DEGs and brown module. The KEGG analysis revealed that 444 core genes were closely associated with specific pathways. PPIs demonstrated that a key module, consisting of 6 genes, was linked to the phagosome pathway. NCF4, identified as an effective biomarker, was selected for diagnosing AS. Bioinformatics analyses indicated that NCF4 could be associated with important clinical markers. RT-PCR and western blotting showed increased expression of NCF4 in AS, which decreased after anti-TNF therapy.ConclusionsAnti-TNF therapy may exert its therapeutic function by inhibiting NCF4 expression, hence controlling the phagosome pathway. NCF4 has the potential to function as a diagnostic and prognostic biomarker for AS.
| S-EPMC10483821 | biostudies-literature
Project description:The current study evaluated 5 patients with ankylosing spondylitis (AS). Patients received intravenous transfusions of umbilical cord mesenchymal stem cells (uMSCs). All therapeutic and adverse responses were assessed and recorded during uMSC therapy. No severe adverse reactions were observed in any of the patients, although a slight transient fever was observed in 3 patients within 2-6 h of intravenous administration of uMSCs. Following treatment, the Bath Ankylosing Spondylitis Disease Activity and Bath Ankylosing Spondylitis Metrology Indices decreased, however the Bath Ankylosing Spondylitis Functional Index increased. The erythrocyte sedimentation rate in 3 patients was reduced and C-reactive protein levels in 1 patient were markedly reduced. The symptoms of AS were alleviated in all patients. The present study indicates that intravenous transfusion of uMSCs is safe and well tolerated by patients and that it effectively alleviates disease activity and clinical symptoms. In the future, a larger cohort of patients with AS should be recruited to enable the systemic evaluation of uMSC therapy.
| S-EPMC5526206 | biostudies-literature
Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.
2012-12-01 | E-GEOD-41038 | biostudies-arrayexpress
Project description:BACKGROUND Ankylosing spondylitis (AS) is a chronic inflammatory disease that predominantly affects the axial skeleton. The ability of anti-TNF-? agents to reduce disease activity in patients with axial spondyloarthritis (axSpA), including AS, has been demonstrated in multiple randomized trials and several meta-analyses. Reports on the efficacy of rituximab in treatment of AS have described good results. We report on a patient with AS who failed anti-TNF-? therapy but showed good clinical improvement with rituximab therapy. CASE REPORT A 38-year-old male patient was diagnosed with AS and showed poor response to sulfasalazine and non-steroidal anti-inflammatory drugs (NSAIDs). Infliximab was initiated with marked improvement as per the Bath ankylosing spondylitis disease activity index (BASDAI). Due to disease flare, the patient was switched to etanercept. He subsequently acquired papillary thyroid cancer and etanercept was discontinued. He underwent a total thyroidectomy followed by radioiodine therapy. For his ongoing active disease, NSAIDs and sulfasalazine were resumed with a lack of response (BASDAI=7.1). Rituximab was started and resulted in significant improvement (BASDAI=2.3). CONCLUSIONS Rituximab can be a potential target therapy for patients who start to lose response to TNF-inhibitors or for those who develop solid malignancies. Further placebo-controlled studies are required.
| S-EPMC5315003 | biostudies-literature
Project description:Background Although TNF inhibitors are well established in ankylosing spondylitis treatment, the majority of studies on TNF inhibitors safety have been performed in rheumatoid arthritis patients. Meanwhile, it seems that TNF inhibitors in ankylosing spondylitis may present a better safety profile than we thought. Objective The aim of our study was to retrospectively investigate the occurrence of adverse events in ankylosing spondylitis patients treated with TNF inhibitors. Setting A single referral center in Poland. Methods Detailed medical history of ankylosing spondylitis patients was obtained during the interview with the patient and by reviewing electronic medical records. Patients treated with TNF inhibitors and patients without TNF inhibitors treatment were compared. Main outcome measure The incidence of adverse events during the 3 months period before the interview. Results A total of 150 patients, 103 in the treatment group and 47 in the control group, were included in the study. There were no differences in the incidence of adverse events, serious adverse events, infections and opportunistic infections between both groups. However, in the treatment group, noninfectious adverse events were significantly less frequent than in control group (RR 0.39, 95% CI 0.23-0.66), with abdominal pain as the most common noninfectious adverse event (RR 0.20, 95% CI 0.07-0.63). The differences in incidence rates of specific infections were not significant, except acute infectious diarrhea which also was less frequent in patients treated with TNF inhibitors (RR 0.17, 95% CI 0.03-0.85). The female gender was significantly associated with any adverse event occurrence (OR 2.36, 95% CI 1.15-4.83). Conclusion TNF inhibitors show a good safety profile in ankylosing spondylitis patients.
| S-EPMC6677866 | biostudies-literature