Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice.
In vitro studies have shown that damaged red cells and apoptotic cells are efficiently phagocytosed by scavenger receptors from macrophages, even under non-opsonizing conditions. Damaged red blood cells are in vivo effectively removed from the blood circulation, but the responsible receptor systems are largely unknown. We used a murine model in which (51)Cr-labeled oxidized red blood cells were injected intravenously, and the cellular uptake sites and the potential involvement of scavenger receptors were analyzed. The decay of damaged red cells was rapid (more than 50% removed within 10 minutes after injection), whereas native red cells were not cleared. The main site of uptake of damaged red cells was the liver Kupffer cells, which contained 24% of the injected dose at 10 minutes after injection. The blood decay and liver uptake were inhibited by typical ligands for scavenger receptors, such as polyinosinic acid, liposomes containing phosphatidylserine, oxidized low-density lipoprotein, and fucoidan, but not by polyadenosinic acid or liposomes without phosphatidylserine. Mice lacking scavenger receptors class A type I and II showed no significant decrease in the ability to take up damaged red cells from the circulation. We conclude that Kupffer cells are mainly responsible for the removal of damaged red cells from the blood circulation, a process mediated by polyinosinic acid- and phosphatidylserine-sensitive scavenger receptors, different from scavenger receptor class A type I and II. Our data indicate that scavenger receptors, as pattern-recognizing receptors, play an important role in vivo in the removal of apoptotic, damaged, or other unwanted cells from the blood circulation. (Blood. 2000;95:2157-2163)
Terpstra
V
V
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, Leiden, The Netherlands.
van Berkel
T J
TJ
D000818:Animals; D004912:Erythrocytes / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000502:physiology*; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D018384:Oxidative Stress; D010477:Perfusion; D010713:Phosphatidylcholines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D008081:Liposomes; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B