Hypothetical model for the effect of stored versus fresh blood transfusion on macrophage differentiation. Under inflammatory conditions such as after transfusion of stored RBCs containing lipids and microparticles, macrophages are polarized toward the classical M1 macrophage activation pathway associated with bactericidal activity and proinflammatory cytokine production conducive of immunostimulation. The transfusion of fresh blood under noninflammatory conditions is associated with less RBC clearance and therefore less loading of macrophages with heme, as well as up-regulation of HO and a shift toward the M2 differentiation pathway, which is associated with immunoregulation through the induction of Tregs.