Arthritis Research & Therapy最新文献

Background: Bone marrow mesenchymal stem cell (BMSC) therapy can significantly improve the outcomes of rheumatoid arthritis (RA). This study explores the protective role of BMSC-derived exosomes (BMSCs-Exos) in RA through modulation of pyroptosis and mitochondrial integrity via the microRNA (miR)-515-5p/Toll-like receptor 4 (TLR4)/NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) pathway.

Methods: Exosomes were isolated from rat BMSCs, with or without miR-515-5p transfection. Exosomes were identified and analyzed through transmission electron microscopy, tunable resistive pulse sensing, and protein profiling via Western blot analysis. An in vitro RA model was established by stimulating RA fibroblast-like synoviocytes (RA-FLSs) with interleukin-1β (IL-1β). Co-culture of RA-FLSs with miR-515-5p-enriched BMSCs-Exos was used to evaluate inflammation, extracellular matrix (ECM) adhesion, migration, and invasion. Dual-luciferase reporter and RNA immunoprecipitation assays were performed to validate the targeting relationship between miR-515-5p and TLR4. Pyroptosis, reactive oxygen species (ROS) generation, and mitochondrial function were assessed. In vivo effects were confirmed using the collagen-induced arthritis (CIA) rat model.

Results: In RA-FLSs, BMSCs-Exos suppressed ECM adhesion, migration, and invasion, and attenuated IL-1β-induced inflammation through the TLR4/NLRP3/GSDMD pathway. BMSCs-Exos inhibited pyroptosis and improved mitochondrial function. Inhibition of miR-515-5p reduced cell viability, caused morphological changes, elevated cytosolic calcium (Ca²⁺), and increased mitochondrial ROS, activating caspase-dependent apoptosis and TLR4/NLRP3/GSDMD-mediated pyroptosis. In CIA rats, BMSCs-Exo treatment significantly alleviated joint damage, reduced pro-inflammatory cytokines, and protected against bone erosion.

Conclusion: BMSCs-Exos ameliorate RA progression by secreting miR-515-5p, which targets the TLR4/NLRP3/GSDMD pathway, thereby inhibiting pyroptosis and preserving mitochondrial homeostasis in RA-FLSs.

The infrapatellar fat pad (IFP) plays a pivotal role in the pathogenesis of knee osteoarthritis (KOA), exhibiting marked histological changes as the disease progresses. However, the intra-tissue variations within KOA-affected IFP remain poorly understood. In this study, we examined IFP tissues from KOA patients at different disease stages, assessing inflammatory damage through histological evaluation via H&E staining. Based on the extent of tissue damage, we classified IFP regions into inflammatory and non-inflammatory layers. Quantitative PCR (qPCR) and immunohistochemical analyses were then employed to compare the expression of joint damage-associated molecules and immune cell infiltration between these two regions. Our results reveal a pronounced inflammatory response in the IFP tissue adjacent to the synovium (inflammatory layer), while the deeper, non-synovial regions (non-inflammatory layer) showed relatively mild inflammation. Additionally, the inflammatory layer exhibited significantly higher secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-8) and adipokines (Leptin, Adiponectin, and FABP4) compared to the non-inflammatory layer. Notably, B cell infiltration was more prominent in the inflammatory layer than other immune cell types, highlighting its potential role in the progression of KOA. These findings underscore the heterogeneity within the IFP and suggest that localized inflammation, particularly B cell involvement, may contribute to the change of IFP and pathophysiology of KOA.

Background: Interstitial lung disease (ILD) is highly prevalent among systemic sclerosis (SSc) patients and is the leading cause of mortality. This study aims to evaluate the independent and combined value of inflammatory markers, coagulation parameters, and autoantibodies for the presence of SSc-ILD.

Methods: A total of 177 patients with SSc were enrolled in this study, including 116 patients with SSc-ILD and 61 without ILD. Multivariate logistic regression was performed to identify independently associated factors for SSc-ILD. The identification efficiency of individual and combined biomarkers was assessed using receiver operating characteristic curves, with the DeLong test applied to compare differences in area under the curve.

Results: The incidence of dcSSc, Raynaud's phenomenon, and digestive system involvement was significantly higher in the SSc-ILD group. Four stepwise models were constructed, and the results of the full-factor model indicated that elevated NLR (neutrophil to lymphocyte ratio), prolonged PT (prothrombin time), and anti-SCL-70 antibody positivity were independent associated factors for SSc-ILD. The combined model of NLR, PT, and anti-SCL-70 yielded an AUC of 0.879 (95% CI: 0.828-0.930), which was significantly greater than any individual marker (P < 0.001), with a sensitivity of 82.6% and a specificity of 85.0%.

Conclusion: NLR, PT, and anti-SCL-70 antibody together form a triad of independent associated factors for SSc-ILD, demonstrating substantial discriminatory potential when considered as a composite indicator.

Background: Idiopathic inflammatory myopathy (IIM) is a chronic autoimmune disorder characterized by muscle inflammation and weakness. If a muscle is already damaged, muscle strength often fails to restore with current treatments. Although, NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) and has been suggested to contribute to the pathogenesis of various disease by inducing ROS production and mitochondrial dysfunction, its role in IIM has not been fully explained.

Methods: Primary myoblasts from IIM patients and non-myopathic controls, as well as human skeletal muscle cells (SkMCs), were cultured under inflammatory conditions induced by interleukin (IL)-15, IL-6, and interferon-gamma (IFN-γ). NOX4 inhibitors, GKT137831 and GLX351322, were administered prior to cytokine stimulation. The effects of NOX4 inhibition were assessed in vitro and in vivo using a C protein-induced myositis (CIM) mouse model.

Results: IIM-derived myoblasts showed impaired myotube formation and elevated NOX4 expression compared to controls. Cytokine stimulation for SkMCs recapitulated key features of inflammatory myopathy, increased NOX4 and myoblast determination protein 1 (MyoD) expression. Treatment with NOX4 inhibitors reduced NOX4 and MyoD levels, restored myotube differentiation, and normalized the elevated oxygen consumption rate (OCR) associated with mitochondrial dysfunction. In the CIM model, NOX4 inhibition significantly reduced muscle inflammation (p < 0.05), preserved muscle mass (p < 0.001), increased cross-sectional area (CSA, p < 0.0001), and improved grip strength (p < 0.01).

Conclusions: We showed that NOX4 is associated with muscle damage in IIM and suggest that its inhibition may have novel therapeutic effect for mitigating muscle damage and disease progression in IIM.

Objectives: Research indicates that low doses of interleukin-2 (IL-2) can effectively mitigate Rheumatoid arthritis (RA) symptoms by promoting Treg cells, while high doses may enhance immune responses and exacerbate the disease. Consequently, this study employed mutated IL-2 to minimize its impact on CD8⁺ T and NK cell activation while preserving its influence on Treg cells.

Methods: We used a previously published mutation sites to construct the murine IL-2 mutants by overlap PCR. Then we assessed its impact on the proliferation and functionality of Treg cells by flow cytometry and PCR. The synergistic effects of mutated IL-2 and MSC on collagen-induced arthritis (CIA) in mice were evaluated through the infusion of lentiviral-transduced umbilical cord-derived mesenchymal stromal cell (UC-MSC) for CIA treatment and through pathological section staining to assess inflammatory joint injury, cartilage destruction, and osteoclast infiltration.

Results: Mutant IL-2 demonstrated targeted enhancement of both the proportion and proliferative activity of Treg cells with a diminished capacity to stimulate the proliferation of CD8⁺ T cells and NK cells relative to wild-type IL-2. Moreover, MSC-mutant IL-2 significantly augmented the proportion of Treg cells compared to either MSC or mutant IL-2 in isolation. Treatment with MSC-mutant IL-2 infusion in CIA mice ameliorated arthritis symptoms and reduced inflammatory infiltration and cartilage damage in their joints.

Conclusion: Mutant IL-2 enhances Treg function and proliferation while exerting reduced effects on CD8⁺ T and NK cell activation. MSC expressing mutant IL-2 demonstrates therapeutic benefits in CIA by increasing the proportion of Treg cells and reducing the proportion of CD8⁺ T cells.

Background: Evidence on the association between sleep disorders and rheumatoid arthritis (RA) remains limited. This study aimed to investigate this relationship in U.S. adults using data from the National Health and Nutrition Examination Survey (NHANES).

Methods: This cross-sectional study included adults aged ≥ 18 years from the 2005-2018 NHANES cycles. A total of 28,040 participants were included. Weighted multivariate logistic regression models were employed to assess the association between sleep disorders and RA. Three models were constructed: an unadjusted model, a minimally adjusted model controlling for demographic variables, and a fully adjusted model incorporating additional lifestyle and clinical covariates. Subgroup analyses were performed to assess the consistency of associations across different population strata, and sensitivity analyses were conducted to confirm the robustness of the results.

Results: Of the 28,040 participants, 4168 (14.32%) were identified as having sleep disorders, and 1589 (4.28%) reported having RA. In the fully adjusted model, sleep disorders were significantly associated with increased odds of RA (OR = 1.76, 95% CI: 1.46-2.13, P < 0.001). Subgroup analyses showed that this positive association persisted across all examined strata, with no significant interactions (P for interaction > 0.05).

Conclusions: In conclusion, our findings indicate a statistically significant association between sleep disorders and the prevalence of RA in U.S. adults. However, given the limitations of the cross-sectional design, causal inferences cannot be made. Future longitudinal and mechanistic studies are warranted to clarify the temporal direction and biological pathways underlying this association.

Objectives: Peripheral helper T (Tph) cells, a recently identified Th cell subset, have been implicated in various autoimmune diseases. However, their role in granulomatosis with polyangiitis (GPA) remains unclear. This study aimed to investigate the potential clinical significance of circulating Tph cells (cTph) in GPA.

Methods: Peripheral blood mononuclear cells were collected from 74 remission GPA-patients, 26 active GPA-patients and 22 age- and sex-matched healthy controls. Flow cytometry was used to quantify cTph cells and their subset distribution. Single-cell multi-omics profiling was performed in an independent cohort (5 remission GPA-patients, 5 active GPA-patients and 5 healthy controls). Plasma IL-21 levels were measured by enzyme-linked immunosorbent assay, and associations between cTph cells and clinical parameters were evaluated.

Results: active GPA-patients showed an increased frequency and absolute number of cTph compared to remission GPA-patients, and both GPA groups exhibited cTph2-skewed distribution compared to healthy controls. Remission GPA-patients with generalized disease exhibited higher cTph frequencies than those with localized disease. cTph cells from active GPA-patients displayed an activated phenotype and a transcriptional profile marked by pro-inflammatory and survival-associated genes. Plasma IL-21 levels did not differ significantly between the three groups. Notably, absolute counts of memory cTph and cTph2 cells correlated positively with clinical markers of disease activity, and were significantly elevated in GPA patients with higher cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) titers.

Conclusions: cTph cells are expanded and exhibit an activated, pro-inflammatory profile with a cTph2-skewed distribution in active GPA-patients. Their association with disease activity may support a potential role in disease pathogenesis and highlight their potential as therapeutic targets, warranting further investigation.

CAR-T cells (CAR-Ts) are genetically engineered T lymphocytes to express a receptor construct bearing an extracellular recognition domain that guides the killing specificity, a transmembrane domain, and an intracellular domain that elicits effector signaling. Upon encountering the target cell, CAR-Ts accomplish their cytolytic effector function directly via engagement of pro-apoptotic pathways and exocytosis of perforin and granzymes, or indirectly via secretion of cytokines that activate NK cells. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 or BCMA, were initially approved for the treatment of late-stage hematologic malignancies. The last five years, mounting evidence from small studies in humans, employing autologous CAR-Ts targeting CD19 to selectively eliminate CD19 + cell subsets from the pool of the B-cell lineage, have revealed acceptable safety profile and encouraging efficacy in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis. Herein, we focus on a series of groundbreaking reports published within 2025 that enlighten the arising transformational potential and the emerging challenges of the CAR-based therapies regarding the management of life-threatening endotypes of autoimmune diseases.