Natural products and immune-cell responses in osteoarthritis: mechanisms, evidence maturity, and translational gaps.

Osteoarthritis (OA) is increasingly recognized as an immune-associated whole-joint disorder characterized by chronic low-grade inflammation, which contributes to joint degeneration, structural deterioration, and persistent pain. Innate and adaptive immune cells, including macrophages, T cells, neutrophils, and mast cells, participate in OA pathogenesis by releasing pro-inflammatory cytokines, reactive oxygen species, and matrix-degrading enzymes, as well as by interacting with chondrocytes, synovial fibroblasts, and subchondral bone cells. Natural products, because of their multi-target pharmacological properties, have emerged as potential modulators of this complex immune microenvironment. This review critically appraises current evidence on natural-product interventions modulating OA-associated immune-cell responses, with particular emphasis on mechanistic evidence, evidence maturity, and translational potential. It further compares evidence across immune-cell populations to identify shared mechanisms, population-specific differences, and key translational gaps. Macrophage- and T-cell-associated responses have the most developed evidence base, with relatively consistent evidence supporting modulation of M1-like/M2-like macrophage phenotypes and the T helper 17 (Th17)/regulatory T (Treg) cell balance. Neutrophil- and mast-cell-associated responses represent emerging or auxiliary areas of evidence, as these immune-cell populations may amplify inflammation and pain through reactive oxygen species production, neutrophil extracellular trap formation, degranulation, and inflammatory mediator release. Evidence for B cells, dendritic cells (DCs), and natural killer (NK) cells remains limited; therefore, these immune-cell populations should currently be regarded as potential research directions rather than established therapeutic targets. Most available data derive from in vitro and animal studies, whereas clinical evidence is largely restricted to peripheral immune-marker changes and short-term symptom improvement. Future studies should integrate local joint immune profiling, functional validation, and stratified clinical designs to clarify the translational potential of natural products in OA immunomodulation.