Ubiquitination and degradation of CD47 enhances macrophage phagocytosis of hemolytic erythrocytes.

The destruction of red blood cells by classical complement activation can form erythrocyte ghosts in immune-mediated hemolysis. However, the mechanisms involved in clearing these membrane remnants remain to be elucidated. In this study, a combination of in vivo models, in vitro macrophage co-culture systems, proteomic screening, and functional validation assays was employed to investigate the cellular processing of erythrocyte ghosts. We demonstrated that erythrocyte ghosts are engulfed by macrophage phagocytosis. Besides, a significant downregulation of CD47, a critical "don't-eat-me" signal, is observed on the membranes of erythrocyte ghosts due to ubiquitin-proteasome-mediated degradation, facilitating their phagocytic removal by macrophages. Moreover, the E3 ubiquitin ligase MARCH 1 was identified as the principal mechanistic regulator governing the loss of CD47. These findings uncover a critical pathway for the efficient clearance of hemolytic remnants, offer alternative perspectives on post-hemolytic immune homeostasis, and suggest potential therapeutic avenues for reducing complications associated with hemolysis.