CD44-mediated copper accumulation drives Ly6Chi macrophages activation in ulcerative colitis.

Ly6Chi macrophages activation plays a significant role in the progression of inflammation. This study aims to elucidate the role of CD44-mediated copper accumulation in driving Ly6Chi macrophages activation in ulcerative colitis (UC). We identified Ly6Chi macrophages and revealed a significant increased proportion in macrophages from scRNA-seq dataset GSE264408. GW2580, which has been validated to effectively suppress the activation of Ly6Chi macrophages, ameliorated symptoms and pathological features in UC mice. Proteomic analysis revealed elevated CD44 and reduced copper export protein ATP7A expression in the colon of UC mice, with a significant correlation between them. Additionally, copper accumulation was observed in BMDMs-derived Ly6Chi macrophages. The CD44 monoclonal antibody IM7 substantially reduced copper accumulation, restored ATP7A protein level, decreased ROS level, and suppressed inflammatory activation in Ly6Chi macrophages. These findings demonstrated that CD44-mediated copper accumulation drives the activation of Ly6Chi macrophages, representing a critical mechanism in the inflammatory pathogenesis of UC.