Trained Immunity Exacerbates Inflammatory Arthritis Progression via Promoting Synovial Fibroblast Ferroptotic Resistance

Abstract Trained immunity induced by β‐glucan insult drives the functional reprogramming of macrophages to the hyperinflammatory status, contributing to developing or maintaining inflammatory diseases. Inflammatory arthritis is characterized by an idiopathically hyperinflammatory response, a phenotype similar to that of trained immunity, and its etiology involves environmental factors such as β‐glucan exposure. However, whether trained immunity contributes to inflammatory arthritis progression, as well as the reciprocal interactions, remains elusive. The study shows that β‐glucan‐induced experimental trained immunity heighten inflammation and arthritis severity in collagen‐induced arthritis (CIA) rat model. Trained macrophages by β‐glucan, upon adoptive transfer, further intensify symptoms. In arthritis progression, trained macrophages reduce fibroblast‐like synoviocytes’ (FLS) lipid peroxidation, lessening sensitivity to iFSP1‐induced ferroptosis through interleukin‐1 beta (IL‐1β)/N‐acetyltransferase 10 (NAT10)/ferroptosis suppressor protein 1 (FSP1) mRNA ac4C modification. A therapeutic approach targeting trained immunity, combining low‐dose iFSP1 and Remodelin, mitigates arthritis severity and restores ferroptosis sensitivity. Additionally, this interplay between CIA induction and β‐glucan training creates a feedback loop reinforcing trained immune memory, accelerating disease deterioration. The findings highlight trained immunity induced by endogenous or exogenous insult, such as β‐glucan, as an unexplored mechanism of inflammation dysregulation in the pathogenesis of inflammatory arthritis, opening avenues for the therapeutic approaches by targeting trained immunity.