Fig. 3: Trained immunity and chronic diseases.

Trained immunity plays a pivotal role in the pathogenesis of several chronic diseases, including ASCVD, CKD, rheumatic diseases and age-related conditions. In ASCVD, various endogenous danger signals, such as WDs, oxLDL, LP(a), hyperglycemia, catecholamines, aldosterone and TMAO, induce trained immunity through the reprogramming of HSPCs and the activation of pathways such as Akt–mTOR, MLL family, RUNX1 and IL-1β. This reprogramming sustains inflammatory responses, contributing to the long-term progression of ASCVD. In CKD, uremic toxins (for example, IS and TMAO), hyperlipidemia and high salt levels activate innate immune cells and even non-immune cells (such as ECs), promoting chronic inflammation and progressive renal damage. Similarly, in rheumatic diseases, including RA, gout and SLE, persistent stimulation by endogenous DAMPs, such as autoantibodies, promotes chronic inflammation through trained immunity. In aging, or immunosenescence, there is a decline in adaptive immunity accompanied by a chronic low-grade systemic inflammatory state, termed inflammaging. Over time, trained immunity in response to sustained DAMPs and chronic inflammatory molecules can amplify this inflammation, increasing susceptibility to chronic inflammatory diseases associated with aging. These mechanisms highlight trained immunity as a critical factor in the development and persistence of inflammation-driven diseases across various organ systems and over the lifespan. The figure was created using BioRender.com.