Macrophage-centred crosstalk with infiltrating immune cells in rheumatoid arthritis and its regulation by mesenchymal stem cells

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by synovitis and progressive joint destruction. The complex network of immune cell interactions plays a crucial role in RA pathogenesis. Pro-inflammatory M1 macrophages initiate and amplify synovial inflammation by releasing cytokines that recruit and activate T cells and neutrophils, stimulate B-cell proliferation and autoantibody production. In contrast, M2 macrophages exert anti-inflammatory effects but are functionally impaired in RA. Macrophage-derived CXCL16 enhances CD4⁺ T-cell recruitment, activated CD4⁺ T cells differentiate into distinct helper T (Th) cell subsets and regulatory T (Treg) cells, both of which contribute to the pathogenesis of RA by producing specific cytokines. B-cells, known for their highly selective antigen uptake capability, process antigens derived from antigen-immunoglobulin immune complexes and subsequently present them to activate T cells and macrophages. They also contribute to chemokine-mediated recruitment, facilitating ectopic lymphoid structure formation and sustained autoantibody responses. Neutrophils, which are essential components of the innate immune system, are the first immune cells to migrate to inflamed sites and initiate defence responses. Significant infiltration of neutrophils has been observed in the synovial fluid of patients with RA, where they interact with macrophages to form neutrophil extracellular traps (NETs). NETs perpetuate citrullinated autoantigen generation and thereby promoting persistent inflammation and joint damage. In recent years, emerging evidence highlights mesenchymal stem cells (MSCs) as potential immunomodulators of regulating the RA microenvironment, by promoting anti-inflammatory phenotype polarisation, inducing T cell differentiation to Tregs, inhibiting the differentiation and proliferation of B cells, neutrophil recruitment and the forming of NETs. This review summarizes the macrophage-centred immunological crosstalk underlying RA, to inform clinical decision-making and contribute to the development of novel treatment strategies for RA by providing insights into the immunopathogenesis of RA and the therapeutic potential of MSCs.