Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Although biologic therapies targeting inflammatory cytokines have improved disease outcomes, many patients fail to achieve sustained remission, highlighting the need for alternative therapeutic strategies. Increasing evidence suggests that RA represents not only excessive inflammatory signaling but also a failure of endogenous regulatory mechanisms that normally restrain immune activation. Central to RA pathogenesis is the activation of inflammatory signaling cascades involving transforming growth factor-β-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB), and the NLRP3 inflammasome, which collectively promote cytokine production, synovial hyperplasia, and cartilage destruction. Recent studies have identified metabolic and neuroimmune pathways as important regulators of these processes. Among them, bile acid-activated signaling through the farnesoid X receptor (FXR) and neural modulation via the cholinergic anti-inflammatory pathway mediated by the α7 nicotinic acetylcholine receptor (α7-nAChR) have emerged as key endogenous mechanisms capable of suppressing inflammatory responses. FXR signaling regulates immune and metabolic pathways, inhibits NF-κB and inflammasome activation, and modulates immune cell differentiation. In parallel, α7-nAChR-mediated cholinergic signaling suppresses cytokine production and limits innate immune activation through neuroimmune communication. Notably, both pathways converge on TAK1-dependent inflammatory signaling. This review highlights the emerging roles of metabolic and neuroimmune regulatory circuits in RA and discusses their therapeutic potential, including opportunities for drug repurposing aimed at restoring endogenous anti-inflammatory pathways.
Senna et al. (Fri,) studied this question.