Chronic Synovial Inflammation Research Articles

Profiling of plasma extracellular vesicles identifies proteins that strongly associate with patient's global assessment of disease activity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and cartilage/bone damage. Intercellular messengers such as IL-1 and TNF play a crucial role in the pathophysiology of RA but have limited diagnostic and prognostic values. Therefore, we assessed whether the protein content of the recently discovered extracellular vesicles (EVs), which have gained attention in the pathogenesis of RA, correlates with disease activity parameters in RA patients. We identified and quantified proteins in plasma-derived EVs (pEVs), isolated by size exclusion chromatography from 17 RA patients by mass spectrophotometry (MS). Quantified protein levels were correlated with laboratory and clinical parameters and the patient's own global assessment of their disease activity (PGA-VAS). In a second MS run, the pEV proteins of nine other RA patients were quantified and compared to those from nine healthy controls (HC). No differences were observed in the concentration, size, and protein content of pEVs from RA patients. Proteomics revealed >95% overlapping proteins in RA-pEVs, compared to HC-pEVs (data are available via ProteomeXchange with identifier PXD046058). Remarkably, in both runs, the level of far more RA-pEV proteins correlated positively to PGA-VAS than to either clinical or laboratory parameters. Interestingly, all observed PGA-VAS positively correlated RA-pEV proteins were associated with the actin-cytoskeleton linker proteins, ezrin, and moesin. Our observation suggests that PGA-VAS (loss of vitality) may have a different underlying pathological mechanism in RA, possibly related to enhanced muscle actin-cytoskeleton activity. Furthermore, our study contributes to the growing awareness and evidence that pEVs contain valuable biomarkers for diseases, with added value for RA patients.

The FTO-CMPK2 Pathway in Fibroblast-like Synoviocytes Modulates Rheumatoid Arthritis Synovial Inflammation and Cartilage Homeostasis via mtDNA Regulation.

In rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by chronic synovial inflammation and progressive cartilage degradation, fibroblast-like synoviocytes (FLS) are key pathogenic players. Current treatments targeting these cells are limited. Our study focused on the Fat Mass and Obesity-associated protein (FTO), known for its roles in cell proliferation and inflammatory response modulation, and its involvement in RA. We specifically examined the inflammatory regulatory roles of FTO and CMPK2, a mitochondrial DNA synthesis protein, in FLS. Utilizing a combination of in vitro and in vivo methods, including FTO inhibition and gene knockdown, we aimed to understand FTO's influence on RA progression and chondrocyte functionality. Our findings showed that increased FTO expression in RA synovial cells enhanced their proliferation and migration and decreased senescence and apoptosis. Inhibiting FTO significantly slowed the disease progression in our models. Our research also highlighted that the FTO-CMPK2 pathway plays a crucial role in regulating synovial inflammation through the mtDNA-mediated cGAS/STING pathway, affecting chondrocyte homeostasis. This study indicates that targeting the FTO-CMPK2 axis could be a promising new therapeutic strategy for managing RA.

Use of Janus Kinase (JAK) Inhibitors in the Treatment of Rheumatoid Arthritis: A Review of Efficacy and Safety Compared to Conventional Therapies

Rheumatoid Arthritis (RA) is a complex autoimmune disorder characterized by chronic synovial inflammation, leading to progressive joint deterioration and substantial morbidity. While conventional disease-modifying antirheumatic drugs (DMARDs) have been the cornerstone of RA management, the emergence of Janus Kinase (JAK) inhibitors has revolutionized the treatment paradigm. This comprehensive review paper analyzes the efficacy, safety, and practical considerations associated with JAK inhibitors in managing RA juxtaposed with conventional therapies. Through an exploration of the mechanism of action, the efficacy of JAK inhibitors in ameliorating disease activity and improving patient outcomes is underscored. The review also addresses the safety concerns surrounding using JAK inhibitors, emphasizing the need to monitor potential adverse events. Furthermore, the paper discusses the role of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and DMARDs in RA management, highlighting their limitations and benefits. Practical clinical recommendations for using JAK inhibitors are elucidated, considering their positioning as a second-line therapy for patients with inadequate response or intolerance to conventional DMARDs. Finally, the abstract emphasizes the importance of ongoing research and post-marketing surveillance to comprehensively evaluate the long-term implications of JAK inhibitors, aiming to optimize their integration within personalized treatment strategies for RA.

Immune cell-specific and common molecular signatures in rheumatoid arthritis through molecular network approaches

Rheumatoid arthritis (RA) is an autoimmune disorder and common symptom of RA is chronic synovial inflammation. The pathogenesis of RA is not fully understood. Therefore, we aimed to identify underlying common and distinct molecular signatures and pathways among ten types of tissue and cells obtained from patients with RA. In this study, transcriptomic data including synovial tissues, macrophages, blood, T cells, CD4+T cells, CD8+T cells, natural killer T (NKT), cells natural killer (NK) cells, neutrophils, and monocyte cells were analyzed with an integrative and comparative network biology perspective. Each dataset yielded a list of differentially expressed genes as well as a reconstruction of the tissue-specific protein-protein interaction (PPI) network. Molecular signatures were identified by a statistical test using the hypergeometric probability density function by employing the interactions of transcriptional regulators and PPI. Reporter metabolites of each dataset were determined by using genome-scale metabolic networks. It was defined as the common hub proteins, novel molecular signatures, and metabolites in two or more tissue types while immune cell-specific molecular signatures were identified, too. Importantly, miR-155-5p is found as a common miRNA in all tissues. Moreover, NCOA3, PRKDC and miR-3160 might be novel molecular signatures for RA. Our results establish a novel approach for identifying immune cell-specific molecular signatures of RA and provide insights into the role of common tissue-specific genes, miRNAs, TFs, receptors, and reporter metabolites. Experimental research should be used to validate the corresponding genes, miRNAs, and metabolites.

Urinary metabolomic biomarker candidates for skeletal muscle wasting in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints, leading to chronic synovial inflammation and local tissue destruction. Extra-articular manifestations may also occur, such as changes in body composition. Skeletal muscle wasting is often observed in patients with RA, but methods for assessing loss of muscle mass are expensive and not widely available. Metabolomic analysis has shown great potential for identifying changes in the metabolite profile of patients with autoimmune diseases. In this setting, urine metabolomic profiling in patients with RA may be a useful tool to identify skeletal muscle wasting. Patients aged 40-70years with RA have been recruited according to the 2010 ACR/EULAR classification criteria. Further, the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) determined the disease activity. The muscle mass was measured by Dual X-ray absorptiometry (DXA) to generate the appendicular lean mass index (ALMI) by summing the lean mass measurements for both arms and legs and dividing them by height squared (kg/height2 ). Finally, urine metabolomic analysis by 1 H nuclear magnetic resonance (1 H-NMR) spectroscopy was performed and the metabolomics data set analysed using the BAYESIL and MetaboAnalyst software packages. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to the 1 H-NMR data, followed by Spearman's correlation analysis. The combined receiver operating characteristic curve (ROC) was calculated, as well as the logistic regression analyses to establish a diagnostic model. The significance level at P<0.05 was set for all analyses. The total set of subjects investigated included 90 patients with RA. Most patients were women (86.7%), with a mean age of 56.5±7.3years old and a median DAS28-CRP of 3.0 (IQR 1.0-3.0). Fifteen metabolites were identified in the urine samples with high variable importance in projection (VIP scores) by MetaboAnalyst. Of these, dimethylglycine (r=0.205; P=0.053), oxoisovalerate (r=-0.203; P=0.055), and isobutyric acid (r=-0.249; P=0.018) were significantly correlated with ALMI. Based on the low muscle mass (ALMI ≤6.0kg/m2 for women and ≤8.1kg/m2 for men) a diagnostic model have been established with dimethylglycine (area under the curve [AUC]=0.65), oxoisovalerate (AUC=0.49), and isobutyric acid (AUC=0.83) with significant sensitivity and specificity. Isobutyric acid, oxoisovalerate, and dimethylglycine from urine samples were associated with low skeletal muscle mass in patients with RA. These findings suggest that this group of metabolites may be further tested as biomarkers for identification of skeletal muscle wasting.

Microplastics aggravates rheumatoid arthritis by affecting the proliferation/migration/inflammation of fibroblast-like synovial cells by regulating mitochondrial homeostasis

Rheumatoid arthritis (RA) is an autoimmune disease involving multiple joints. RA is a systemic disease characterized by chronic synovial inflammation and destruction of articular cartilage and bone. As a new pollutant, microplastics can enter the body through the respiratory and digestive tract and cause health damage. However, to date, the impact of microplastics on RA has not been revealed. Therefore, in the current research, we explored the impact of microplastics on RA. First, FLS (fibroblast-like synoviocytes) from RA was isolated and identified. FLS has been used as a cell model in vivo to study the potential impact of microplastics on FLS. Therefore, a series of biochemical experiments have been carried out, such as indirect immunofluorescence, western blotting and flow cytometry. First, we found that microplastics promote the proliferation of RA-FLSs through the MTT assay and the detection of cell proliferation markers and the cell cycle analysis through flow cytometry. On this basis, further research showed that microplastics also promoted the invasion and migration ability of RA-FLSs through Transwell experiments. In addition, microplastics also promote the secretion of inflammatory factors in RA-FLSs. In in vivo studies, the effect of microplastics on RA cartilage damage was evaluated. The results showed that RA cartilage damage was aggravated by microplastics, as determined by Alcian blue, toluidine blue and safranin O-fast green staining. Current research shows that microplastics, as a new pollutant, can promote sustained damage in RA.

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

BackgroundThe p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53β is driving aggressive disease in RA.MethodsUsing RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53β. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software.ResultsElevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53β mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of ‘activated fibroblasts’ together with elevated levels of Δ133p53β.ConclusionsInduction of Δ133p53β in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53β could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53β could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

The Role of Leptin and Adiponectin in Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease, characterized by chronic synovial inflammation and destruction of cartilage and bone, results in varying degrees of deformity and functional disability. Previous research has shown that there is a link between adipokines and RA, but also other systemic diseases such as cardiovascular disease and diabetes mellitus. Adipokines are biologically active substances, which are predominantly or exclusively secreted from adipocytes of adipose tissue, or other adipose tissue cells such as: preadipocytes, immune cells infiltrated in AT, or other cell types within this tissue. These molecules play a significant role in energy homeostasis and metabolism regulation, and are also involved in chronic inflammation and metabolic dysfunctions. Some of the adipokines act like hormones in glucose homeostasis and appetite regulation, while others, like cytokines, support the link between obesity and insulin resistance with the immune system and the inflammatory process. However, the clear role of adipokines in pathological conditions has not yet been established. This review will focus on current knowledge about the role of the two most prominent adipokines, leptin and adiponectin, in the pathogenesis of RA.

Rheumatoid arthritis and mitochondrial homeostasis: The crossroads of metabolism and immunity.

Rheumatoid arthritis is an autoimmune disease characterized by chronic symmetric synovial inflammation and erosive bone destruction. Mitochondria are the main site of cellular energy supply and play a key role in the process of energy metabolism. They possess certain self-regulatory and repair capabilities. Mitochondria maintain relative stability in number, morphology, and spatial structure through biological processes, such as biogenesis, fission, fusion, and autophagy, which are collectively called mitochondrial homeostasis. An imbalance in the mitochondrial homeostatic environment will affect immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling. These biological processes are involved in the onset and development of rheumatoid arthritis. In this review, we found that in rheumatoid arthritis, abnormal mitochondrial homeostasis can mediate various immune cell metabolic disorders, and the reprogramming of immune cell metabolism is closely related to their inflammatory activation. In turn, mitochondrial damage and homeostatic imbalance can lead to mtDNA leakage and increased mtROS production. mtDNA and mtROS are active substances mediating multiple inflammatory pathways. Several rheumatoid arthritis therapeutic agents regulate mitochondrial homeostasis and repair mitochondrial damage. Therefore, modulation of mitochondrial homeostasis would be one of the most attractive targets for the treatment of rheumatoid arthritis.

Telomeres Length Variations in a Rheumatoid Arthritis Patients Cohort at Early Disease Onset and after Follow-Up.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial joint inflammation, progressive disability, premature immune aging, and telomere length (TL) shortening. The objective of the study was to study TL changes in patients at early disease onset and after follow-up. Relative leukocyte TL (rLTL) was measured by quantitative polymerase chain reaction (qPCR) in 88 at-admission patients (AAP) with < 1 year of symptoms onset, self-compared after follow-up, and a reference group of sex- and age-matched healthy individuals. Correlations between rLTL percentage change after variable disease exposure time (DET) and clinical laboratory disease activity markers and treatments were assessed. Non-parametrical statistics were applied, considering < 0.05 p-value significant. The median (p25, p75) rLTL was lower in patients after DET (0.61, 0.49-0.70) than in AAP (0.64, 0.50-0.77), p = 0.017. Furthermore, telomeres at early stages of RA were shorter than in the reference group (0.77, 0.59-0.92; p = 0.003). HLA-DRB1*04 allele carrier status did not significantly affect rLTL at an early stage and after follow-up. The patients' rLTL shortening was mainly associated with longer at-admission telomeres (OR 16.2, 95%CI: 3.5-74.4; p < 0.0001). At follow-up, RA patients showed significantly shorter rLTL than AAP, particularly in those AAP with longer telomeres, disregarding disease activity and treatments, denoting an rLTL shortening effect influenced by age, DET, and native rLTL.

The Relationship Between Porphyromonas Gingivalis and Rheumatoid Arthritis: A Meta-Analysis.

Rheumatoid arthritis (RA) is a systematical autoimmune disease, characterized by chronic synovial joint inflammation and hurt. Porphyromonas gingivalis(P. gingivalis) can cause life-threatening inflammatory immune responses in humans when the host pathogenic clearance machinery is disordered. Some epidemiological studies have reported that P. gingivalis exposure would increase the prevalence of RA. However, the results remain inconsistent. Therefore, a meta-analysis was done to systematically analyze the relationship between P. gingivalis exposure and the prevalence of rheumatoid arthritis. Database including Cochrane Library, Web of Science, PubMed, and EMBASE were searched for published epidemiological articles assessed the relationship between P. gingivalis and RA. Obtained studies were screened based on the predefined inclusion and exclusion criteria. The overall Odds Ratios (ORs) of incorporated articles were pooled by random-effect model with STATA 15.1 software. The literature search returned a total of 2057 studies. After exclusion, 28 articles were included and analyzed. The pooled ORs showed a significant increase in the risk of RA in individuals with P. gingivalis exposure (OR = 1.86; 95% CI: 1.43-2.43). Subgroup analysis revealed that pooled ORs from populations located in Europe (OR = 2.17; 95% CI: 1.46-3.22) and North America (OR = 2.50; 95% CI: 1.23-5.08) were significantly higher than that from population in Asia (OR = 1.11; 95% CI: 1.03-1.20). Substantial heterogeneity was observed but did not significantly influence the overall outcome. In conclusion, our results indicated P. gingivalis exposure was a risk factor in RA. Prompt diagnosis and management decisions on P. gingivalis antimicrobial therapy would prevent rheumatoid arthritis development and progression.

Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that orchestrates multiple pathogeneses in RA in a suppressive manner. UHRF1 expression was remarkably upregulated in synovial fibroblasts (SFs) from arthritis model mice and patients with RA. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate controls. Uhrf1-deficient SFs also exhibited enhanced apoptosis resistance and upregulated expression of several cytokines, including Ccl20. In patients with RA, DAS28, CRP, and Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration stabilized UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SFs can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.

Source and hub of inflammation: The infrapatellar fat pad and its interactions with articular tissues during knee osteoarthritis.

Knee osteoarthritis, the most prevalent degenerative joint disorder worldwide, is driven by chronic low-grade inflammation and subsequent cartilage degradation. Clinical data on the role of the Hoffa or infrapatellar fat pad in knee osteoarthritis are, however, scarce. The infrapatellar fat pad is a richly innervated intracapsular, extrasynovial adipose tissue, and an abundant source of adipokines and proinflammatory and catabolic cytokines, which may contribute to chronic synovial inflammation, cartilage destruction, and subchondral bone remodeling during knee osteoarthritis. How the infrapatellar fat pad interacts with neighboring tissues is poorly understood. Here, we review available literature with regard to the infrapatellar fat pad's interactions with cartilage, synovium, bone, menisci, ligaments, and nervous tissue during the development and progression of knee osteoarthritis. Signaling cascades are described with a focus on immune cell populations, pro- and anti-inflammatory cytokines, adipokines, mesenchymal stromal cells, and molecules derived from conditioned media from the infrapatellar fat pad. Understanding the complex interplay between the infrapatellar fat pad and its neighboring articular tissues may help to better understand and treat the multifactorial pathogenesis of osteoarthritis.

A Review of Metabolomic Profiling in Rheumatoid Arthritis: Bringing New Insights in Disease Pathogenesis, Treatment and Comorbidities.

Metabolomic analysis provides a wealth of information that can be predictive of distinctive phenotypes of pathogenic processes and has been applied to better understand disease development. Rheumatoid arthritis (RA) is an autoimmune disease with the establishment of chronic synovial inflammation that affects joints and peripheral tissues such as skeletal muscle and bone. There is a lack of useful disease biomarkers to track disease activity, drug response and follow-up in RA. In this review, we describe potential metabolic biomarkers that might be helpful in the study of RA pathogenesis, drug response and risk of comorbidities. TMAO (choline and trimethylamine oxide) and TCA (tricarboxylic acid) cycle products have been suggested to modulate metabolic profiles during the early stages of RA and are present systemically, which is a relevant characteristic for biomarkers. Moreover, the analysis of lipids such as cholesterol, FFAs and PUFAs may provide important information before disease onset to predict disease activity and treatment response. Regarding therapeutics, TNF inhibitors may increase the levels of tryptophan, valine, lysine, creatinine and alanine, whereas JAK/STAT inhibitors may modulate exclusively fatty acids. These observations indicate that different disease modifying antirheumatic drugs have specific metabolic profiles and can reveal differences between responders and non-responders. In terms of comorbidities, physical impairment represented by higher fatigue scores and muscle wasting has been associated with an increase in urea cycle, FFAs, tocopherols and BCAAs. In conclusion, synovial fluid, blood and urine samples from RA patients seem to provide critical information about the metabolic profile related to drug response, disease activity and comorbidities.

Efficient and automatic synthesis of TSPO PET ligand [18F]-GE-180 and its application in rheumatoid arthritis model

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic synovial inflammation, which ultimately leads to joint deformity and dysfunction. [18F]-GE-180 is a specific PET tracer of the 18 kDa translocator protein (TSPO), which is overexpressed on activated macrophages, and proposed as a biomarker of inflammation. Our study addresses the need to streamline the automatic synthesis of [18F]-GE-180 to make it more accessible for routine production and widespread clinical evaluation and application. The nucleophilic radiofluorination was performed on an AllinOne synthesis module by SPE purification method, and the formulated [18F]-GE-180 was obtained in non-decay corrected radiochemical yields of 69 ± 1.8% in 32 min. PET/CT imaging in animal model showed that [18F]-GE-180 highly concentrated in joints from RA rats. This methodology facilitates efficient synthesis of [18F]-GE-180 in a commercially available synthesis module and shows potential diagnosis performance in RA models.

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis.

We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of proNGF on fibroblast-like synoviocytes (FLS), which play a central role in modulating local immune responses and in activating pro-inflammatory pathways. Using single cell RNA sequencing in synovial tissues from active and treatment-naïve rheumatoid arthritis (RA) patients, we demonstrated that p75NTR and sortilin, which form a high affinity receptor complex for proNGF, are highly expressed in PRG4pos lining and THY1posCOL1A1pos sublining fibroblast clusters in RA synovia but decreased in RA patients in sustained clinical remission. In ex vivo experiments we found that FLS from rheumatoid arthritis patients (RA-FLS) retained in vitro a markedly higher expression of p75NTR and sortilin than FLS from osteoarthritis patients (OA-FLS). Inflammatory stimuli further up-regulated p75NTR expression and induced endogenous production of proNGF in RA-FLS, leading to an autocrine activation of the proNGF/p75NTR pathway that results in an increased release of pro-inflammatory cytokines. Our data on the inhibition of p75NTR receptor, which reduced the release of IL-1β, IL-6 and TNF-α, further confirmed the key role of p75NTR activation in regulating inflammatory cytokine production. In a set of ex vivo experiments, we used RA-FLS and cultured them in the presence of synovial fluids obtained from arthritis patients that, as we demonstrated, are characterized by a high concentration of proNGF. Our data show that the high levels of proNGF present in inflamed synovial fluids induced pro-inflammatory cytokine production by RA-FLS. The blocking of NGF binding to p75NTR using specific inhibitors led instead to the disruption of this pro-inflammatory loop, reducing activation of the p38 and JNK intracellular pathways and decreasing inflammatory cytokine production. Overall, our data demonstrate that an active proNGF/p75NTR axis promotes pro-inflammatory responses in synovial fibroblasts, thereby contributing to chronic synovial inflammation, and point to the possible use of p75NTR inhibitors as a novel therapeutic approach in chronic arthritis.

Three-dimensional spatial transcriptomics uncovers cell type localizations in the human rheumatoid arthritis synovium

The inflamed rheumatic joint is a highly heterogeneous and complex tissue with dynamic recruitment and expansion of multiple cell types that interact in multifaceted ways within a localized area. Rheumatoid arthritis synovium has primarily been studied either by immunostaining or by molecular profiling after tissue homogenization. Here, we use Spatial Transcriptomics, where tissue-resident RNA is spatially labeled in situ with barcodes in a transcriptome-wide fashion, to study local tissue interactions at the site of chronic synovial inflammation. We report comprehensive spatial RNA-Seq data coupled to cell type-specific localization patterns at and around organized structures of infiltrating leukocyte cells in the synovium. Combining morphological features and high-throughput spatially resolved transcriptomics may be able to provide higher statistical power and more insights into monitoring disease severity and treatment-specific responses in seropositive and seronegative rheumatoid arthritis.

Polyene Phosphatidylcholine Interacting with TLR-2 Prevents the Synovial Inflammation via Inactivation of MAPK and NF-κB Pathways.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disease that causes cartilage and bone damage or even disability, seriously endangering human health. Chronic synovial inflammation has been shown to play a vital role in disease sustainability. Therefore, downregulation of synovial inflammation is considered to be an effective discipline for RA therapy. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent, which was observed to inhibit inflammation in macrophages and prevent collagen-induced arthritis (CIA) of rats in our previous study. However, the underlying mechanism remains unclear. The present study further reported that PPC can inhibit synovial inflammation. In lipopolysaccharide (LPS)-stimulated primary synovial fibroblasts (SFs) of mice, PPC significantly decreased pro-inflammatory cytokines production while increasing anti-inflammatory cytokines level. In this process, PPC downregulated the expression of TLR-2 and their downstream signaling molecules such as MyD88, p-ERK1/2, p-JNK1/2, and p-P38 in MAPK pathway and p-IκBα and NF-κB-p65 in NF-κB pathway. Moreover, the inhibitory effect of PPC on the above molecules and cytokines was weakened after pre-treatment with TLR-2 agonist Pam3CSK4. In addition, PPC lost its anti-inflammatory effect and its suppressing capabilityon MAPK and NF-κB pathways in TLR-2-/- primary SFs after exposure to LPS. Collectively, this study demonstrated that PPC can alleviate synovial inflammation through TLR-2-mediated MAPK and NF-κB pathways, which can be proposed to be a potential drug candidate for RA prevention.

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.

Bioinformatics-based study to identify immune infiltration and inflammatory-related hub genes as biomarkers for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose principal pathological change is aggressive chronic synovial inflammation; however, the specific etiology and pathogenesis have not been fully elucidated. We downloaded the synovial tissue gene expression profiles of four human knees from the Gene Expression Omnibus database, analyzed the differentially expressed genes in the normal and RA groups, and assessed their enrichment in functions and pathways using bioinformatics methods and the STRING online database to establish protein-protein interaction networks. Cytoscape software was used to obtain 10 hub genes; receiver operating characteristic (ROC) curves were calculated for each hub gene and differential expression analysis of the two groups of hub genes. The CIBERSORT algorithm was used to impute immune infiltration. We identified the signaling pathways that play important roles in RA and 10 hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. The diagnostic value of these 10 hub genes for RA was confirmed using ROC curves and expression analysis. Adcy2, Cxcl13, and Ccr5 are strongly associated with RA development. The study also revealed that the differential infiltration profile of different inflammatory immune cells in the synovial tissue of RA is an extremely critical factor in RA progression. This study may contribute to the understanding of signaling pathways and biological processes associated with RA and the role of inflammatory immune infiltration in the pathogenesis of RA. In addition, this study shows that Adcy2, Cxcl13, and Ccr5 have the potential to be biomarkers for RA treatment.