Robust erythrophagocytosis leads to macrophage apoptosis via a hemin-mediated redox imbalance: role in hemolytic disorders

MP from the RES are responsible for the clearance of senescent RBC. Although the frequency of senescent RBC is low under steady-state conditions, it increases dramatically during hemolytic disorders, resulting in enhanced erythrophagocytosis. As erythrophagocytosis has been involved in MP dysfunction and as certain hemolytic disorders associate to MP apoptosis, a possible link between erythrophagocytosis and the viability of phagocytes was investigated herein. To mimic hemolytic disorders, two distinct in vitro models, artificially oxidized RBC and DSRBC, were chosen to study the erythrophagocytosis impact on the viability of J774A.1 MP. Although CRBC were weakly phagocytosed and did not affect MP viability significantly, erythrophagocytosis of oxidized RBC and DSRBC was robust and resulted in a sharp decrease of MP viability via apoptosis. Under these conditions, Hb-derived HE was shown to be involved in the induction of apoptosis. Moreover, oxidized RBC, DSRBC, and HE generated ROS species, which were responsible for the apoptosis of MP. Furthermore, HO-1, strongly induced in response to treatment with oxidized RBC, DSRBC, or HE, was shown to protect MP partially against apoptosis, suggesting that robust erythro-phagocytosis may exceed the detoxification capabilities of MP. Taken together, these results suggest that enhanced erythrophagocytosis associated to hemolytic disorders leads to MP apoptosis in vitro and may have critical implications for the control of malaria infection and for the exacerbated susceptibility to bacterial infections during hemolytic disorders. J. Leukoc. Biol. 89: 159-171; 2011.