Autoimmunity最新文献

G protein-coupled receptor 183 (GPR183) has been indicated to mediate the migration and localisation of immune cells in T cell-dependent antibody responses. Systemic lupus erythematosus (SLE) is a canonical autoimmune disease involving B cell-mediated tolerance destruction and excessive pathogenic autoantibody production, in which multiple GPCRs play a role. To date, there has been no systematic study regarding the expression of GPR183 in lymphocyte subsets of SLE patients. In this research, firstly, we observed the expression trends of GRP183 in various T and B cell subsets in human tonsil tissues. These lymphocyte subsets include CD4⁺, CD8⁺, naïve T, effector T, Tfh, activated Tfh, Th1, Th2, Th17, Treg, CD19⁺CD27^-, CD19⁺CD27⁺, naïve B, germinal centre B, memory B, and plasma cells. Further, compared with healthy controls (HCs), GPR183 expression levels in above peripheral blood lymphocyte subsets of patients with SLE were reduced overall. The differential expression of GPR183 expression between inactive and active SLE patients indicates that GPR183 expression may be concerned with the disease activity of SLE. This was further confirmed through the strong negative correlation with SLEDAI score and positive correlation with serum complement protein C3, C4 and C1q levels. Further receiver operating characteristic (ROC) curve analysis revealed that GPR183 expression in circulating CD27^-IgD⁺ B cells may be beneficial in distinguishing between inactive and active SLE patients. In addition, type I interferon stimulation could down-regulate the expression of GPR183 in peripheral blood T and B cell subsets. Aberrant expression of GPR183 may provide some novel insights into disease activity prediction and underlying pathogenesis of SLE.

The inflammasome AIM2 regulates multiple aspects of innate immune functions and serves as a critical mediator of inflammatory responses. AIM2 inflammasome activation leads to the production of pro-inflammatory cytokines, IL-1β and IL-18 and participates triggering a pyroptosis response needed to counteract excessive cell proliferation. In addition, AIM2 expression and activation is wide regulated since alteration in its activity may derived in pathological consequences. Consequently, deregulated AIM2 activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of AIM2 inflammasome, as well as its contribution in rheumatoid arthritis and systemic lupus erythematous pathology. Finally, we highlight the participation of the AIM2-inflammasome at the level of joint in rheumatoid arthritis and at kidney in systemic lupus erythematous. The development of therapeutic strategies based on modulation of AIM2-inflammasome activity should have a tissue-specific focus.

Background: Circular RNAs (circRNAs) are demonstrated to play vital roles in human diseases, including rheumatoid arthritis (RA). Therefore, this research aimed to explore the effects of hsa_circRNA_0025908 (circ_0025908) on RA.

Methods: RNA expression of circ_0025908, microRNA-650 (miR-650), and Signal peptide-CUBepidermal growth factor-like containing protein 2 (SCUBE2) were assessed by real-time quantitative polymerase chain reaction; protein expression of SCUBE2, apoptosis- and invasion-related proteins was evaluated by western blot assay. Functional assays were performed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide, 5-ethynyl-2'-deoxyuridine, transwell, flow cytometry, and enzyme linked immunosorbent assay assays. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays confirmed the interaction relationship among circ_0025908, miR-650, and SCUBE2.

Results: Circ_0025908 was overexpressed in synovial tissues and fibroblast-like synoviocytes (FLS) from RA patients. Inhibition of circ_0025908 repressed proliferation, migration, invasion, inflammation, and cell cycle progression, while induced apoptosis in the FLS isolated from RA patients (FLS-RA), accompanied with increased Bax, cleaved caspase-3 and E-cadherin, but declined Bcl-2, N-cadherin and Vimentin. MiR-650 was a target of circ_0025908, and SCUBE2 was a target for miR-650. Silencing of miR-650 could overturned above effects of circ_0025908 knockdown in FLS-RA, whereas its overexpression could mimic those effects by downregulating SCUBE2. Additionally, SCUBE2 expression could be positively regulated by circ_0025908 and inversely regulated by miR-650. Notably, Pearson's correlation analysis confirmed the linear correlation among circ_0025908, miR-650 and SCUBE2 in these RA tissues.

Conclusion: Circ_0025908 inhibition can suppress FLS-RA dysfunctions through targeting miR-650/SCUBE2 axis, suggesting a new potential therapeutic clue for RA patients.

Objective: Endometrial carcinoma (EC) is a common malignant tumour in women. Berberin (BBR) is an alkaloid with anti-tumour activity, and circular RNA (circRNAs) has been extensively studied in cancers. However, whether BBR regulates the development of EC by regulating circular RNA zinc finger protein 608 (ZNF608) is unknown.

Methods: Different concentrations of BBR were used to treat endometrial cancer cells. A quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess the expression of circ_ZNF608, microRNA-377-3p (miR-377-3p) and cyclooxygenase 2 (COX2). The expression of COX2 protein was detected by western blot. The effect of circ_ZNF608 in BBR-treated EC cells was verified by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, transwell, and flow cytometry. The effect of BBR and circ_ZNF608 on tumour growth was evaluated by xenograft tumour model in vivo.

Results: Berberine can inhibit the proliferation and metastasis of EC cells and promote apoptosis, which is related to the concentration. Circ_ZNF608 and COX2 were abnormally increased, while the levels of miR-377-3p were reversed in EC tissues and cells. Overexpression of circ_ZNF608 can restore the inhibitory effect of BBR on EC cells. In addition, circ_ZNF608 restored the inhibitory effect of BBR on EC cells by inhibiting the expression of miR-377-3p. Similarly, MiR-377-3p/COX2 can regulate the tumour progression of EC under BBR. Finally, BBR can inhibit the growth of endometrial carcinoma in vivo.

Conclusion: BBR was found to inhibit EC via the circ_ZNF608/miR-377-3p/COX2 axis, which is helpful in endometrial carcinoma.

Osteoarthritis is thought to be a NLRP3-related disease. NEK7 is an essential mediator for NLRP3 inflammasome activation. This study aimed to demonstrate whether NEK7 has regulatory roles in the pathogenesis of osteoarthritis. C57BL/6 mice were subjected to anterior cruciate ligament transection osteoarthritis (ACLT) for constructing animal models of osteoarthritis. Injection of adeno-associated virus (AAV) expressing NEK7-specific shRNA into the knee joints of mice, following of which immunohistochemistry, qRT-PCR, western blotting, Safranin-O Fast Green staining, ELISA, and co-immunoprecipitation were performed to determine the effects of NEK7. NEK7 was highly expressed in the joint tissues of ACLT mice. As compared with shScr, AAV delivery of NEK7 shRNA significantly inhibited cartilage degeneration, OARSI score, and serum CTX-II and COMP levels. AAV delivery of NEK7 shRNA downregulated the expression of matrix-degrading enzymes (ADAMTS-4, MMP3, and MMP13) and upregulated the expression of ECM-related molecules (SOX9, collagen II, and aggrecan). In addition, AAV delivery of NEK7 shRNA alleviated ACLT-induced synovial inflammation, as was evidenced by the decreased levels of TNF-α, IL-6, IL-1β, and IL-18 and increased levels of IL-10. In the joint tissues of ACLT mice, NEK7 interacted with NLRP3 proteins. AAV delivery of NEK7 shRNA inhibited the protein interaction, and thereby inhibited the activation of the NLRP3 inflammasome. AAV delivery of NEK7 shRNA has no significant effects on cartilage degeneration and synovial inflammation in Nlrp3^-/- mice. In conclusion, knockdown of NEK7 exerted anti-osteoarthritic effects, possibly via inhibiting the activation of the NLRP3 inflammasome. This study provided a novel mechanism of NEK7-NLRP3 interaction affecting osteoarthritis.

Background: Regulatory B cells (Bregs) are a subset of B cells that secrete interleukin 10 (IL-10) and play a vital role in suppressing the immune response. The aim of this study was to evaluate the proportion of Bregs in patients with thymoma.

Methods: The proportions of subgroups of Bregs in 23 patients with thymoma and 15 healthy controls were detected by flow cytometry. The serum IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α levels of the subjects were measured using a cytometric bead array (CBA).

Results: The proportions of circulating IL-10⁺ B cells, IL-10⁺CD24^hiCD38^hi Bregs, and IL-10⁺CD24^hiCD27⁺ Bregs and the serum IL-10 level were significantly higher in patients with thymoma than in the control group and were negatively correlated with the Karnofsky Performance Scale (KPS) score. The serum levels of cytokines IL-2, IL-6, IFN-γ, and TNF-α were higher and serum IL-17A level was lower in patients with thymoma. Patients with advanced-stage thymoma exhibited significantly higher proportions of IL-10-producing Bregs and a higher serum IL-10 level. After tumour resection, the frequency of circulating IL-10⁺CD24^hiCD38^hi Bregs and the serum IL-10 level were significantly decreased in patients with thymoma. The serum IL-10 levels exhibited the best accuracy in assessing the risk of thymoma occurrence in this study.

Conclusions: The expression of IL-10 produced by Bregs is increased in patients with thymoma, particularly those with advanced-stage disease, which may suggest that Bregs are involved in the pathogenesis and progression of thymoma.

Background: The pathogenesis of osteoarthritis (OA), an endemic and debilitating disease, remains unclear. The study aimed to reveal the role of circular RNA cyclin dependent kinase 14 (circCDK14) in OA development and the underlying mechanism.

Methods: Human chondrocytes were stimulated by 10 ng/mL interleukin-1β (IL-1β) to mimic OA cell model. The RNA expression of circCDK14, microRNA-1183 (miR-1183) and kruppel like factor 5 (KLF5) was checked through quantitative real-time polymerase chain reaction. Western blot was employed to detect protein expression. Cell viability, proliferation and apoptosis were investigated by cell counting kit-8, 5-Ethynyl-29-deoxyuridine and flow cytometry analysis, respectively. Starbase online database was performed to identify the interaction between miR-1183 and circCDK14 or KLF5. Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis.

Results: CircCDK14 and KLF5 expression were significantly decreased, while miR-1183 was increased in OA cartilage tissues and IL-1β-treated chondrocytes in comparison with controls. CircCDK14 overexpression attenuated the inhibitory effect of IL-1β treatment on cell proliferation and the promoting effects on cell apoptosis and extracellular matrix degradation. Additionally, miR-1183 was targeted by circCDK14, and miR-1183 mimics reversed circCDK14-mediated actions in IL-1β-treated chondrocytes. The knockdown of KLF5, a target mRNA of miR-1183, also rescued the effects of miR-1183 inhibitors in IL-1β-induced chondrocytes. Moreover, circCDK14 could induce KLF5 expression by interacting with miR-1183. Further, exosomal circCDK14 had a high diagnostic value in OA.

Conclusion: CircCDK14 reintroduction assuaged IL-1β-caused chondrocyte damage by the miR-1183/KLF5 pathway, providing a diagnostic biomarker for OA.