Scavenger endothelial cells alleviate tissue damage by engulfing toxic molecules derived from hemolysis

Hemolysis induces tissue damage by releasing cellular contents into the plasma. It is widely accepted that hemolysis-derived toxic molecules are cleared by macrophages or metabolized in hepatocytes. In zebrafish, we found that scavenger endothelial cells (SECs), a specialized endothelium with remarkable endocytosis capability, engulf both macromolecular hemoglobin (Hb) and small molecular unconjugated bilirubin (UCB), two primary toxic byproducts of hemolysis. These engulfment processes are mediated by the scavenger receptor Stab2. To demonstrate the protective function of SECs during hemolysis, we employed a zebrafish model of erythropoietic porphyria, characterized by excessive protoporphyrin IX (PPIX) accumulation due to ferrochelatase mutation, leading to light-sensitive hemolysis and larva death. We found that SECs facilitate the clearance of excess PPIX via Stab2, thereby mitigating PPIX-induced larval mortality. In addition, mouse SECs possess a conserved capability of scavenging Hb/UCB/PPIX. In conclusion, our study identifies SECs as a detoxification system during physiological and pathological hemolysis, shedding light on their protective role against hemolysis-induced damage.