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

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.