Hsa_circ_0000652 Aggravates Inflammation by Activation of Macrophages and Enhancement of OX40/OX40L Interaction in Ankylosing Spondylitis.
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ABSTRACT:
SUBMITTER: Song M
PROVIDER: S-EPMC8716807 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4+ T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB.
| S-EPMC6018058 | biostudies-literature
Project description:Macrophages activation is crucial in pathogenesis of rheumatic diseases like ankylosing spondylitis (AS). Circular RNAs (circRNAs)-induced macrophage-associated inflammation participates in many autoimmune diseases but remains elusive in AS. Here, we verified increased expression of circIFNGR2 in peripheral blood mononuclear cells from patients with AS and its expression levels were correlated with the AS severity. In vitro assays revealed that circIFNGR2 enhances macrophage proliferation, and regulates M1/M2 macrophage polarization and NF-κB/Akt pathways. We identified that circIFNGR2 promoted the expression of iNOS/TNFα and M1 polarization, and restrained M2 polarization by sponging miR-939. Additionally, the RNA-binding protein, eIF4A3, was found to enhance the production of circIFNGR2. Interestingly, miR-939 attenuated joint damage in collagen-induced arthritis mice, whereas circIFNGR2 reversed this effect. Our findings highlight the pro-inflammatory roles of eIF4A3-induced circIFNGR2 in AS by modulating macrophage-associated inflammation through miR-939.
| S-EPMC10372825 | biostudies-literature
Project description:Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.
| S-EPMC8281657 | biostudies-literature
Project description:ObjectivesThis study aims to investigate the relationship between disease activity, dietary phytochemical index (DPI), and serum total oxidant status (TOS) and total antioxidant status (TAS) in patients with ankylosing spondylitis (AS).Patients and methodsBetween August 2020 and January 2021, a total of 37 patients (23 males, 14 females; mean age: 39.3±9.4 years; range, 21 to 61 years) with AS and 36 age-, sex-, and body mass index-matched healthy individuals (24 males, 12 females; mean age: 37.9±8.9 years; range, 20 to 60 years) were included. Serum TAS (μmoLTroloxEq/L) and TOS (μmoL H2O2Eq/L) measurements were performed and the oxidative stress index (OSI) was calculated. Dietary evaluation was made from a one-day dietary record and DPI was calculated.ResultsSerum TAS level in AS patients was significantly lower than the healthy group (p=0.003). Serum TOS level was similar in both groups. The OSI of patients was significantly higher than the controls (p=0.035). The mean DPI, polyunsaturated fatty acid, n-3 fatty acid, and vitamin C intake of patients were significantly lower than controls (p=0.042, p=0.033, and p=0.022, respectively). A moderate positive correlation was found between the TAS level and DPI of the control group (r=0.352, p=0.035). According to medications, no significant difference was seen between the groups in terms of patients' characteristics, DPI, and laboratory tests and there was no correlation between DPI, TAS, TOS, and OSI.ConclusionLower DPI and lower n-3 fatty acid and vitamin C intake in patient group demonstrated that patients with AS should pay more attention to their diet to increase serum antioxidant status.
| S-EPMC9326390 | biostudies-literature
Project description:T regulatory (Treg) cells play a role in the suppression of immune responses, thus serving to induce tolerance and control autoimmunity. Here, we explored whether Treg cells influence the immediate hypersensitivity response of mast cells (MCs). Treg cells directly inhibited the FcvarepsilonRI-dependent MC degranulation through cell-cell contact involving OX40-OX40L interactions between Treg cells and MCs, respectively. When activated in the presence of Treg cells, MCs showed increased cyclic adenosine monophosphate (cAMP) concentrations and reduced Ca(2+) influx, independently of phospholipase C (PLC)-gamma2 or Ca(2+) release from intracellular stores. Antagonism of cAMP in MCs reversed the inhibitory effects of Treg cells, restoring normal Ca(2+) responses and degranulation. Importantly, the in vivo depletion or inactivation of Treg cells caused enhancement of the anaphylactic response. The demonstrated crosstalk between Treg cells and MCs defines a previously unrecognized mechanism controlling MC degranulation. Loss of this interaction may contribute to the severity of allergic responses.
| S-EPMC2590499 | biostudies-literature
Project description:Rationale: Inflammation plays a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Protein tyrosine phosphatase receptor type O truncated isoform (PTPROt) is an integral membrane protein that has been identified in osteoclasts, macrophages, and B lymphocytes. However, its relationship between inflammation and NASH is largely unknown. Herein, we aimed to study the function of PTPROt in NASH progression. Methods: We established a NASH mouse model in wild-type (WT), PTPRO knockout mice by western diet (WD) and methionine-choline-deficient diet (MCD). In addition, MCD-induced NASH model was established in BMT mice. Moreover, we determined the expression of PTPROt in liver macrophages in human subjects without steatosis, with simple steatosis, and with NASH to confirm the relationship between PTPROt and NASH. In vitro assays were also performed to study the molecular role of PTPROt in NASH progression. Results: Human samples and animal model results illustrated that PTPROt is increased in liver macrophages during NASH progression and is positively correlated with the degree of NASH. Our animal model also showed that PTPROt in liver macrophages can enhance the activation of the NF-κB signaling pathway, which induces the transcription of genes involved in the inflammatory response. Moreover, PTPROt promotes the transcription of pro-oxidant genes and inhibits antioxidant and protective genes via increased activation of the NF-κB signaling pathway, thereby causing an increased level of reactive oxygen species (ROS) and damaged mitochondria. This triggers the NLRP3-IL1β axis and causes a heightened inflammatory response. Notably, PTPROt partially limits inflammation and ROS production by promoting mitophagy, which participates in a negative feedback loop in this model. Conclusions: Our data strongly indicate that PTPROt plays a dual role in inflammation via the NF-κB signaling pathway in liver macrophages during NASH. Further studies are required to explore therapeutic strategies and prevention of this common liver disease through PTPROt.
| S-EPMC7196286 | biostudies-literature
Project description:MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.
| S-EPMC8931122 | 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:Whole blood RNA-sequencing data from 5 AS patients who met 1984 AS criteria and 3 healthy human were obtained to gain insight into the potential mechanism of ankylosing spondylitis.
2021-11-10 | GSE181364 | GEO
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.
2012-12-01 | GSE41038 | GEO