Immune-metabolic crosstalk in rheumatoid arthritis: mediation effects of plasma metabolites on inflammatory cytokines.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory condition defined by synovitis and progressive joint damage. The connection between inflammatory cytokines, molecules, and RA is still poorly understood despite the information combining both immune dysregulation and metabolic reprogramming to its pathophysiology.

Methods: A two-sample Mendelian randomization (MR) analysis was carried out using summary statistics from the largest-scale genome-wide association study (GWAS) to examine the link between 91 inflammatory cytokines and RA risk. Metabolite pathways were identified through mediation analysis. Multiple MR Methods including inverse variance weighting (IVW) were used for causal estimation and the hypothesis was verified by sensitivity analysis.

Results: The analysis results showed that there was a causal association between six inflammatory cytokines and RA. Among them, HGF and IL-10RA increased the risk of RA, while CXCL9, EN-RAGE, IFN-γ and CCL8 showed protective effects. These associations were validated using multiple MR methodologies, including inverse-variance weighting, MR-Egger regression, and leave-one-out sensitivity analyses. Further mediation MR analysis revealed seven metabolite-mediated pathways of inflammatory cytokines and RA. Specifically, the protective effect of CXCL9 was achieved in part by reducing plasma eicosapentaenoic acid (EPA; 20:5n3) levels (mediating effect = -0.007; proportion mediated = 8.10%). The protective effect of EN-RAGE was mediated by a decrease in the level of salicyluric glucuronide (mediating effect = -0.015; 12.70%). IFN-γ reduced the risk of RA through two independent metabolic pathways: reducing the level of 1-arachidonoyl-glycerol-3-phosphocholine (20:4n6) levels (mediating effect = -0.005; 4.67%), and increasing the ratio of glycine-to-pyridoxal (mediating effect = -0.020; 19.60%). In contrast, IL-10RA increases the risk of RA by increasing 3,7-dimethylurate (mediating effect = 0.011; 12.50%) and decreasing N, N-dimethylalanine levels (mediating effect = 0.010; 11.70%). The protective effect of CCL8 was mediated by the reduction of specific sphingomyelin species (d17:2/16:0, d18:2/15:0) (mediating effect = -0.012; 12.30%).

Conclusions: The results of this study not only confirmed the causal role of specific inflammatory cytokines in the pathogenesis of RA from a genetic perspective, but more importantly, for the first time, systematically revealed the specific plasma metabolite mediating pathways that connect these inflammatory cytokines to RA. These findings more specifically link the immune dysregulation of RA to metabolic remodeling, especially the protective role of IFN-γ through glycine/pyridoxal balance, and the pathway of IL-10RA through purine metabolites to affect risk, providing novel and mechanistic insights into the immunometabolic network of RA. We believe that these specific intermediate metabolites are expected to be potential candidate targets for future targeted therapies or intervention strategies, aiming to precisely regulate the interaction between inflammation and metabolism.