Summary of the principal findings of the work of Liu et al. Hemolytic disorders, such as SCD, are characterized by intravascular hemolysis, leading to release of cell-free heme. Liu et al show that free heme can act on monocyte and macrophages in liver, triggering release of IFN-I. The latter can induce further recruitment of monocytes and their differentiation in the liver into macrophages proficient at phagocytosis of erythrocytes. Moreover, IFN-I induced expression of IgG Fc-binding receptor CD64 on macrophages. Both the increased number of macrophages in liver and higher expression of high-affinity IgG receptor can boost phagocytosis and destruction of erythrocytes.