Trained immunity in chronic, relapsing and low-grade joint inflammation

Trained immunity is a form of innate immune memory mediated by metabolic and epigenetic reprogramming that promotes sustained inflammatory responses. Accumulating evidence implicates a role for maladaptive trained immunity in sustaining inflammation and promoting disease progression across distinct forms of inflammatory joint disease, including rheumatoid arthritis, gout, calcium pyrophosphate deposition disease and osteoarthritis. Inflammatory cytokines, damage-associated patterns and metabolic signals can induce long-lasting inflammatory programmes in both immune cells, such as monocytes and macrophages, and non-immune cells within the joint, such as chondrocytes and synovial-like fibroblasts. Trained immunity also provides a potential mechanistic link between joint inflammation and associated systemic complications, including increased cardiovascular risk. Therapeutic strategies targeting the metabolic and epigenetic pathways that underlie trained immunity could offer opportunities to limit chronic inflammation, prevent structural damage and reduce disease-associated comorbidities.