Rheumatoid arthritis (RA) is an auto-immune disease characterized by inflammatory episodes and joint degradation. Activated macrophages produce large amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines, which damage chondrocytes and destroy the cartilage matrix. Therefore, a promising therapeutic strategy for the treatment of RA is to inhibit the secretion of pro-inflammatory cytokines and ROS to promote macrophage polarization and facilitate cartilage repair. In this paper, an active targeting nanomedicine based on metal-phenolic networks (MPNs) is constructed to re-polarize activated macrophages for RA therapy. Sr2+ and Cu2+ are first coordinated with tannic acid (TA) to prepare TSC, and TNF-α siRNA is loaded into TSC via simple ultrasonic treatment to obtain TSSC. Finally, TSSC is coated with M1 macrophage membrane (termed as TSSC@M1) to enhance its inflammatory targeting ability. TSSC@M1 can actively target macrophages by releasing TA, Cu2+, and TNF-α siRNA to synergistically scavenge ROS and inhibit the expression of TNF-α to induce macrophage polarization, while Sr2+ can further protect cartilage. In the collagen-induced arthritis (CIA) mouse model, TSSC@M1 can accumulate at inflamed joints and alleviate RA symptoms by modulating macrophage phenotype and repairing cartilage. Overall, TSSC@M1 NPs offer a promising and safe approach to treat RA.

BackgroundDiclofenac etalhyaluronate (DF-HA, SI-613/ONO-5704) is a conjugate of hyaluronic acid (HA) and diclofenac (DF), and its intra-articular injection is widely used for the treatment of osteoarthritis in Japan. While novel mechanisms of cartilage protection by DF-HA have been identified, a comprehensive analysis of the biological responses unique to DF-HA has not yet been conducted.DesignWe used an RNA sequencing (RNA-seq) method to comprehensively analyze gene expression in the knee joint cartilage of arthritic rats and cytokine-stimulated chondrocytes. For the mechanistic analysis of DF-HA, genes that were downregulated or upregulated by DF-HA, HA, or DF were extracted. Pathway analysis was then performed on genes that specifically varied with DF-HA treatment.ResultsIn the cartilage of rats with collagen-induced arthritis, treatment with DF-HA, but not DF or HA, suppressed the extracellular matrix (ECM) remodeling pathway and promoted the parathyroid hormone/parathyroid hormone-related peptide receptor-mediated pathway, which regulates chondrocyte differentiation and bone/cartilage development. In cytokine-stimulated chondrocytes, DF-HA similarly suppressed the ECM remodeling pathway; specifically, gene expression changes in IGFBP4, MMP10, MMP13, and TIMP1 were consistent with those observed in vivo.ConclusionRNA-seq analysis of cartilage in arthritic rats and cytokine-stimulated chondrocytes provided molecular mechanistic insights, indicating that DF-HA treatment induced cartilage protection through the suppression of ECM remodeling.

Helix-Guarded Molecular Clips Confer Robust Scavenging of Intra-Articular Cell-Free DNA for the Treatment of Rheumatoid Arthritis.

Reducing individual inflammatory factors does not always translate into clinical efficacy in rheumatoid arthritis (RA), an autoimmune disease characterized by joint inflammation. Proinflammatory M1 macrophages are a key driver of the hyperinflammatory joint microenvironment, which also promotes the progression of RA. Here we show that folate-receptor-targeted photosynthetic nanothylakoid (FA-PEG-NTK)-based phototherapy reprogrammes macrophages from M1 to anti-inflammatory M2, and successfully remodels the inflammatory RA microenvironment. The nanothylakoids were sourced from plant-derived thylakoids and developed by surface modification with distearoyl phosphoethanolamine-polyethylene glycol (PEG) via hydrophobic interactions to preserve their photocatalytic enzymes. We show that upon light irradiation in a mouse macrophage model of inflammation, the FA-PEG-NTK system generates oxygen and nicotinamide adenine dinucleotide phosphate, alleviating hypoxia and reducing reactive oxygen species. This rebalances the oxidative stress in M1 macrophages, thereby remodelling the inflammatory microenvironment in RA. We also show that in a collagen-induced arthritis rat model, FA-PEG-NTK-mediated phototherapy notably alleviated synovial hyperplasia and enhanced bone and cartilage regeneration, outperforming the clinical treatment methotrexate, with no apparent side effects.

Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes.

ABSTRACTThe mechanistic link between periodontitis (PD) and rheumatoid arthritis (RA) remains poorly understood. This study aimed to investigate whether PD‐associated salivary microbiota exacerbates RA via an “oral‐gut‐immune axis.” We performed 16S rRNA sequencing and untargeted metabolomics on saliva from healthy controls and patients with PD, RA, or both (PD‐RA). Salivary microbiota from PD patients or healthy controls were transplanted into collagen‐induced arthritis (CIA) mice. Clinically, PD‐RA patients exhibited enrichment of periodontal pathogens (e.g., Porphyromonas sp., Prevotella sp.) and pro‐inflammatory lipid metabolites. In vivo, transplantation of PD microbiota into CIA mice significantly worsened arthritis, evidenced by higher clinical scores (3.5 ± 0.5 vs. 2.3 ± 0.4, p < 0.05) and greater joint destruction. Mechanistically, PD microbiota colonized the gut, impaired intestinal barrier integrity, and induced systemic immune dysregulation, characterized by an increased splenic Th17/Treg cell ratio and elevated serum IL‐6 and C‐reactive protein. These changes were associated with altered gut microbial metabolism, including reduced short‐chain fatty acids and enhanced arachidonic acid pathways. Our findings delineate a pathogenic oral‐gut‐immune axis in which PD microbiota aggravates RA, underscoring the importance of integrated oral and systemic disease management.

Inhibition of ALOX5-dependent ferroptosis by 6-C-methylquercetin: a potential therapeutic approach for alleviating rheumatoid arthritis.

Folate-guided AIE nanoparticles integrate macrophage-targeted fluorescence imaging and photodynamic immunomodulation in rheumatoid arthritis.

Reactive oxygen species production by monocytes negatively correlates with disease activity in rheumatoid arthritis.

The protective role of TRIM16 in rheumatoid arthritis: mechanisms of modulating ferroptosis.

Therapeutic potential of polysaccharides in inflammation: current insights and future directions.

Geniposide alleviates rheumatoid arthritis by inhibiting pyroptosis by regulating the miR-223-3p/NLRP3 Axis.

Rheumatoid arthritis (RA) patients often develop comorbid RA-associated interstitial lung disease, which is a severe extra-articular manifestation associated with high incidence and mortality rates. Nintedanib, an oral small-molecule tyrosine kinase inhibitor, has shown promise in clinical studies by mitigating disease progression and enhancing lung function among RA-associated interstitial lung disease patients. Adverse reactions to nintedanib are closely linked to its blood concentration, potentially leading to discontinuation due to gastrointestinal side effects and elevated liver enzymes. However, existing research has yet to delve into the pharmacokinetic impact of RA on nintedanib. Therefore, we established a collagen-induced arthritis rat model to examine how RA influences the pharmacokinetics of nintedanib. Additionally, we conducted Caco-2 transport experiments to explore potential factors contributing to these pharmacokinetic alterations. Our findings reveal that nintedanib's pharmacokinetics change in collagen-induced arthritic rats at different disease stages compared to the control group. This alteration results in a notable increase in blood drug concentration and significant changes in pharmacokinetic parameters such as maximum serum concentration (Cmax), AUC0-t, AUC0→∞, and time to reach peak concentration (Tmax). The outcomes from the Caco-2 transport experiments indicate that interleukin 6 stimulation impedes nintedanib efflux, aligning with the observed pharmacokinetic alterations. Further Western blot experiments suggest that the changes in nintedanib's pharmacokinetics are associated with reduced expression of P-glycoprotein. Moreover, our findings suggest that RA may reduce intestinal P-glycoprotein expression by activating the C-Jun N-terminal kinase signaling pathway. SIGNIFICANCE STATEMENT: Rheumatoid arthritis significantly increases the drug concentration of nintedanib. These data suggest that rheumatoid arthritis may be caused by reducing the expression of P-glycoprotein by affecting the C-Jun N-terminal kinase signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder with complex pathophysiology. Disease cycle involves immune/inflammatory cells (macrophages, CD4 + , T, and B-cells) that directly/indirectly augment NF- κB mediated inflammation/oxidative stress and vice-versa creating a vicious loop that worsens disease. Inhibition of NF-κB signalling has emerged as a target for RA alleviation thus, this study evaluates the capability of Cassia fistula leaf extracts in supressing NF-κB signalling and contribution of sennoside B in extract efficacy. Extracts were prepared and its anti-inflammatory (IL-1β, TNF-α, IL-6, IL-17a), anti-oxidant (NO, MDA, catalase, reduced glutathione), NF-κB inhibition potential, and its effect on joint microstructure was evaluated on collagen-induced arthritis. Extracts were characterized using LC-MS and effect of sennoside B (anthraquinone glycoside detected in extracts) on NF-κB signalling was evaluated on LPS stimulated peritoneal macrophages. Ethanolic extract of C. fistula leaf significantly inhibited NF-κB signalling (transcriptional/translational level), which led to significant reduction of inflammatory mediators (IL-1β, TNF-α, IL-6, IL-17a), and restored redox imbalance (NO, MDA, catalase, and reduced glutathione). Reduced NF-κB activity supressed tissue remodelling and osteoclastogenesis markers (MMP-2, MMP-9, MMP-13, and RANKL) which resulted in joint microstructure safe-guarding, also reflected as reduced paw swelling, paw volume and disease score significantly. Sennoside B showed strong anti-inflammatory and NF-κB inhibition against LPS-stimulated peritoneal macrophages. Ethanolic extract of C. fistula leaves alleviate RA by modulating NF-κB mediated inflammation and oxidative stress and disrupts the disease worsening feedback cycle. Sennoside B's capability to suppress NF-κB production/activation also plays an important role in increasing extract efficacy.

Dysbiosis of the gut microbiota plays a key role in the pathogenesis of rheumatoid arthritis (RA). However, it is still unclear whether the classic prescription Er Miao San (EMS) can exert therapeutic effects on RA by regulating the gut microbiota. In this study, we investigated whether EMS alleviates collagen-induced arthritis (CIA) by modulating the gut microbiota and its metabolites. We demonstrated that EMS significantly reduced arthritis severity, paw swelling, and systemic inflammation in CIA mice. In addition, 16S rRNA sequencing analysis revealed that EMS restored gut microbiota homeostasis, as evidenced by an increased abundance of Bacteroidetes, and a decreased Bacteroidetes/Firmicutes ratio. Crucially, antibiotic depletion of the gut microbiota abolished the protective effects of EMS, whereas fecal microbiota transplantation (FMT) from EMS-treated donors replicated its anti-arthritic efficacy, confirming the indispensable role of the microbiota. Measurement of short-chain fatty acids (SCFAs) further revealed a significant increase in the microbial metabolite butyrate following EMS treatment. Subsequent supplementation with sodium butyrate mimicked the therapeutic effects of EMS, ameliorating joint inflammation and cartilage damage. Mechanistically, butyrate enhanced the expression of intestinal tight junction proteins (ZO-1 and occludin), thereby restoring intestinal barrier integrity. Collectively, our results demonstrate that EMS exerts its anti-arthritic effects by modulating the gut microbiota-butyrate-intestinal barrier axis, highlighting the critical value of microbial metabolites in RA treatment. This study provides novel insights into the mechanism of EMS and suggests the therapeutic potential of butyrate for RA.

Integrative multi-omics reveals that Salvia miltiorrhiza active fraction ameliorates rheumatoid arthritis in rats via inhibiting inflammation and ferroptosis.

Dual-targeted hybrid micelles mediated by VCAM-1 suppress synovial angiogenesis in rheumatoid arthritis.

The Interleukin-33 (IL-33) has a strong[AL1] pro-inflammatory effect on collagen-induce arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying mechanism remains unclear. In this study, we investigated the presence of the IL-33 receptor suppression of tumorigenicity 2 (ST2) on T follicular helper (Tfh) cells and its impact on CIA through regulation of Tfh cells and germinal center (GC) B cells. [AL1]LE: Please check if the corresponding author's telecommunications data are correctly captured/indicated. In vitro studies involved treating polarized Tfh cells with IL-33 to analyze its effects on Tfh differentiation by measuring ST2, PD-1, and CXCR5 expression using flow cytometry. C57BL/6J mice were immunized with keyhole limpet hemocyanin (KLH) and divided into three groups: control, KLH-only, and KLH+IL-33. Additionally, ST2-/- mice were immunized with KLH. The ratio of T follicular regulatory (Tfr)/Tfh in spleens was examined by flow cytometry. DBA/1 mice were divided into four groups: control, CIA-only, CIA+low-does IL-33(days 1-5), and CIA+high-does IL-33 (days 1-5 and 21-25). Arthritis severity was assessed using arthritis score, hematoxylin and eosin (H&E) staining, and Safranin O-Fast Green staining. Flow cytometry measured CXCR5/PD-1 expression on CD4+T cells and GL-7/FAS expression on B cells in draining lymph nodes (LN). ELISA was used to detect serum[AL1] IgG, IgM and anti-bovine collagen type II IgG2a and IgG2b antibodies concentrations. [AL1]LE: Please check if the section headings are assigned to appropriate levels. In vitro experiments showed that IL-33 promoted Tfh differentiation and survival. IL-33 disrupted the Tfr/Tfh balance in the KLH model. In CIA, IL-33 exacerbated arthritis severity by enhancing Tfh cell proliferation in LNs and significantly altering GC B cell development and antibody production. This study reveals a novel mechanism by which IL-33 exacerbates RA, suggesting its pro-inflammatory effects are mediated through Tfh cell polarization and GC activation. Key Points • The IL-33/ST2 axis promotes Tfh cell differentiation and viability. • IL-33 exacerbates arthropathy and enhances germinal center reactions in CIA mice. • IL-33 increases the Tfh cell ratio and ST2 expression on Tfh cells in CIA mice. • The IL-33/ST2 axis disrupts the Tfr/Tfh balance in KLH-immunized mice.

To analyze the molecular mechanism of Xixian Pills for treatment of rheumatoid arthritis (RA). Forty-eight rats were randomized into 6 groups (n=8), including a normal control group, a collagen-induced arthritis (CIA) model group, 3 Xixian Pills treatment (200, 400 and 800 mg/kg) groups, and a Tripterygium glycosides tablet (TGT) treatment group. In the latter 4 groups, the rats were treated with daily gavage of Xixian Pills or TGT 2 weeks after CIA modeling for 3 consecutive weeks. The differentially expressed proteins in high-dose Xixian Pills group and the model group compared with the normal control group were screened based on the tandem mass spectrometry tag (TMT) technology, and the core targets and signaling pathways were analyzed. The immune cell infiltration and gene expression data were analyzed using ggplot2 and tidyverse packages, and the correlation coefficients between the core targets and the immune cells were calculated. The CIA rats showed significantly increased serum levels of TNF-α and IL-6 and lowered serum IL-10 level. Treatments with high- and medium-dose Xixian Pills and TGT all significantly reduced serum TNF‑α and IL-6 and increased IL-10 levels in CIA rats. Proteomic analysis identified 160 differential proteins between the model group and high-dose Xixian Pills group, and the core targets included CCL5, STAT1, GZMB and IL7R. The areas under the ROC curve of CCL5 and STAT1 were both greater than 0.9. Immunohistochemical and immunofluorescence staining revealed increased levels of CCL5 and STAT1 in the ankle joints of CIA rats, which were significantly decreased after treatment with Xixian Pills. Treatment with Xixian Pills offers protection of the joints in CIA rats possibly by inhibiting joint inflammation via regulating protein expressions of CCL5 and STAT1.

Targeted delivery of Prussian blue modified exosomes to CD90-expressing synovial fibroblasts for Rheumatoid arthritis immunotherapy