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Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis, joint damage and deformity. A newly described type of cell death, ferroptosis, has an important role in the pathogenesis of RA. However, the heterogeneity of ferroptosis and its association with the immune microenvironment in RA remain unknown. Synovial tissue samples from 154 RA patients and 32 healthy controls (HCs) were obtained from the Gene Expression Omnibus database. Twelve of twenty-six ferroptosis-related genes (FRGs) were differentially expressed between RA patients and HCs. Furthermore, the patterns of correlation among the FRGs were significantly different between the RA and HC groups. RA patients were classified into two distinct ferroptosis-related clusters, of which cluster 1 had a higher abundance of activated immune cells and a corresponding lower ferroptosis score. Enrichment analysis suggested that tumor necrosis factor-α signaling via nuclear factor-κB was upregulated in cluster 1. RA patients in cluster 1 responded better to anti-tumor necrosis factor (anti-TNF) therapy, which was verified by the GSE 198520 dataset. A diagnostic model to identify RA subtypes and immunity was constructed and verified, in which the area under the curve values in the training (70%) and validation (30%) cohorts were 0.849 and 0.810, respectively. This study demonstrated that there were two ferroptosis clusters in RA synovium that exhibited distinct immune profiles and ferroptosis sensitivity. Additionally, a gene scoring system was constructed to classify individual RA patients.

Background Numerous studies have demonstrated that NLRP3 is involved in the pathogenesis of inflammatory bowel disease (IBD). Mesenchymal stem cells (MSCs) have been highlighted as new candidates for treating IBD based on their immunomodulatory properties, including regulation of the NLRP3 inflammasome. However, the role of NLRP3 in shaping the immunoregulatory function of MSCs remains unclear. In this study, we demonstrated that NLRP3 influences the therapeutic effect of MSCs on colitis in an inflammasome-independent manner. Methods MSCs were isolated from the femurs of male C57/B6 mice or Nlrp3 KO mice, identified by osteogenic adipogenic differentiation assay and flow cytometry. In vitro, WT and Nlrp3 KO MSCs were treated with LPS, then the supernatant was collected; WT MSCs were stimulated with different concentrations of NLRP3-specific inhibitor MCC950, and the level of IL-10 was detected in the supernatant; Detect gene expression levels by RNA sequencing; Use Seahorse to detect cellular oxidative phosphorylation (OXPHOS) and glycolysis levels; The expression of glucose transporter 1 (Glut1) in MSCs was detected by Western blot; WT MSCs were stimulated with different concentrations of Glut1 inhibitor BAY876, and the level of IL-10 was detected. In vivo, DSS-induced colitis was treated with WT or Nlrp3 KO MSCs, body weight changes were monitored daily, measure colon length and collect colons for further evaluation; Then DSS-induced colitis was treated with pretreated MSCs, such as BAY876 pretreated WT MSCs or Glut1-overexpressed Nlrp3 KO MSCs (OE-Glut1), then the experimental operation is as above. Results Nlrp3 knockout did not alter MSC phenotypes, but promoted osteogenic differentiation. Further investigation indicated that deletion of Nlrp3reduced the production of the IL-10 in MSCs, leading to an impaired protective effect on DSS-induced colitis. Mechanistically, the deficiency of Nlrp3 downregulated Glut1 expression and glycolysis activation in MSCs, which reduced IL-10 production. Subsequently, overexpressing Glut1 in Nlrp3 KO MSCs recovered their therapeutic effect dampened due to Nlrp3 deletion. Conclusions These results improve the current understanding of the molecular mechanisms underlying the therapeutic effectiveness of MSCs and provide a basis for optimizing MSC-based therapeutic strategies for immune-mediated diseases.

Introduction Acute exacerbation (AE) is a devastating complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and leads to high mortality. This study aimed to investigate the incidence, risk factors, and prognosis of acute exacerbation of rheumatoid arthritis-associated interstitial lung disease (AE-RA-ILD). Methods PubMed, EMBASE, Web of Science, and Medline were searched through 8 February 2023. Two independent researchers selected eligible articles and extracted available data. The Newcastle Ottawa Scale was used to assess the methodological quality of studies used for meta-analysis. The incidence and prognosis of AE-RA-ILD were investigated. Weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) and pooled odds ratios (ORs) with 95% CIs were calculated to explore the risk factors of AE in RA-ILD. Results Twenty-one of 1,589 articles were eligible. A total of 385 patients with AE-RA-ILD, of whom 53.5% were male, were included. The frequency of AE in patients with RA-ILD ranged from 6.3 to 55.6%. The 1-year and 5-year AE incidences were 2.6–11.1% and 11–29.4%, respectively. The all-cause mortality rate of AE-RA-ILD was 12.6–27.9% at 30 days and 16.7–48.3% at 90 days. Age at RA diagnosis (WMD: 3.61, 95% CI: 0.22–7.01), male sex (OR: 1.60, 95% CI:1.16–2.21), smoking (OR: 1.50, 95% CI: 1.08–2.08), lower forced vital capacity predicted (FVC%; WMD: −8.63, 95% CI: −14.68 to − 2.58), and definite usual interstitial pneumonia (UIP) pattern (OR: 1.92, 95% CI: 1.15–3.22) were the risk factors of AE-RA-ILD. Moreover, the use of corticosteroids, methotrexate, and biological disease-modifying anti-rheumatic drugs, was not associated with AE-RA-ILD. Conclusion AE-RA-ILD was not rare and had a poor prognosis. Age at RA diagnosis, male sex, smoking, lower FVC%, and definite UIP pattern increased the risk of AE-RA-ILD. The use of medications, especially methotrexate and biological disease-modifying anti-rheumatic drugs, may not be related to AE-RA-ILD. Registration CRD42023396772.