Because key cellular subsets and interaction programs may still retain partial plasticity during the early and middle stages of disease, stage-adapted modulation of these pathogenic networks may help restore synovial immune homeostasis, promote remission, delay disease progression, and reduce irreversible tissue damage.
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive cartilage and bone destruction. Within the RA synovial microenvironment, resident synoviocytes, mesenchymal stem cells, fibroblasts, adipocytes, vascular-associated cells, and diverse immune cell populations form a dynamic interaction network through direct contact and paracrine mediators, including cytokines, chemokines, complement components, and extracellular vesicles. This review summarizes how these cellular interactions drive RA along a pathological continuum from early autoimmune initiation, through middle-stage inflammatory amplification and synovial hyperplasia, to late fibrosis, pannus formation, dysregulated bone remodeling, and irreversible structural damage. Particular emphasis is placed on the dynamic balance between pathogenic cellular circuits and immunoregulatory programs within the synovial microenvironment, which helps determine whether the joint remains in an inflammatory-active state, re-enters a remission-associated and relatively rebalanced state, or progresses toward remission failure and structural injury. We further discuss the major signaling pathways that mediate these interactions, especially NF-κB, MAPK, JAK-STAT, TGF-β/Smad, and Wnt/β-catenin signaling, highlighting how pathway crosstalk contributes to inflammatory persistence, loss of tissue plasticity, and progressive remodeling. Importantly, because key cellular subsets and interaction programs may still retain partial plasticity during the early and middle stages of disease, stage-adapted modulation of these pathogenic networks may help restore synovial immune homeostasis, promote remission, delay disease progression, and reduce irreversible tissue damage. A deeper understanding of stage-specific cellular programs and interaction networks may therefore provide a stronger theoretical basis for mechanism-informed precision therapies in RA.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by persistent synovial inflammation, autoantibody production, cartilage damage, and bone erosion. Biologic disease-modifying antirheumatic drugs (DMARDs) and targeted small-molecule therapies have improved disease control, but durable remission remains difficult for many patients. Low-grade synovitis and structural damage may continue despite treatment. Extracellular vesicles (EVs) may contribute to this residual activity by carrying signals that are not captured by soluble cytokine measurements alone. In the inflamed joint, EVs are released by fibroblast-like synoviocytes, macrophages, neutrophils, endothelial cells, chondrocytes, and osteoclast precursors. Their cargo includes citrullinated proteins, inflammatory mediators, miRNAs, lipids, and matrix-degrading enzymes and often reflects the state of the parent cell. This mini-review examines EV biogenesis, movement across the synovial barrier, and uptake by recipient cells in RA. It evaluates evidence linking EV cargo to NF-κB, MAPK, JAK-STAT, and cGAS-STING signaling; innate and adaptive immune activation; fibroblast-like synoviocyte invasion; and osteoclast differentiation. We also assess the current evidence for EVs as biomarkers and therapeutic vehicles, with particular attention to methodological and translational limitations.
Feng Luo, Xuemei Yuan, Heng Zhou et al.· Frontiers in Immunology· 0 citations
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and progressive joint destruction. Although conventional therapies effectively alleviate clinical symptoms, they are largely incapable of reversing irreversible joint damage and the underlying immune dysregulation. Mesenchymal stem cells (MSCs), with their dual capabilities in immunomodulation and tissue repair, have emerged as a promising new therapeutic strategy. This review delineates how MSCs and their derived extracellular vesicles exert multifaceted anti-inflammatory and immunosuppressive effects in RA. Locally, these mechanisms include modulating the Treg/Th17 cell balance, inhibiting the proliferation and invasion of fibroblast-like synoviocytes, and regulating the RANKL/OPG system to suppress osteoclast activity, while orchestrating the repair and regeneration of damaged joints primarily through the secretion of trophic factors and paracrine regulation of local bone metabolism. Importantly, beyond these local effects, this review highlights the novel ‘gut-MSC-immune’ axis, elucidating the potential pathway through which MSCs might systemically modulate immune homeostasis by influencing gut microbiota composition and mucosal barrier integrity. Although preliminary clinical trials have demonstrated a favorable safety profile and potential therapeutic feasibility of MSC-based interventions, its therapeutic outcomes are significantly influenced by patient heterogeneity and the hostile inflammatory microenvironment. To address these clinical bottlenecks and overcome interpatient therapeutic heterogeneity, we discuss the synergistic potential of microbiota-targeted interventions combined with MSC therapy. Finally, key priorities for future research are proposed, including standardizing MSC preparation protocols, optimizing administration regimens, and validating long-term efficacy and safety via large-scale multicenter clinical trials—efforts that will ultimately accelerate the clinical translation and clinical application of precision MSC-based therapy for RA.
Liujiayu Li, Jieling Wu, Yutong Wu et al.· Frontiers in Immunology· 0 citations
It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
Tong Wang, Wei Jiang, Xingxu Chen et al.· Frontiers in Immunology· 0 citations
Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging “resolution therapies” that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies.
