Clearance of Sickle Hemoglobin By Hepatic Endothelial Cells Is Critical to Protect Against Hemolysis Induced Organ Damage in Sickle Cell Anemia

Sickle cell disease (SCD) is a homozygous recessive genetic disorder caused by a single nucleotide point mutation in the β-globin gene. Hemolysis and accumulatio of cell free hemoglobin is a predominant pathophysiology associated with multi organ damage including liver damage in SCD. The mononuclear phagocytic system plays a critical role in sickle hemoglobin (HbS) clearance. However, the role of liver sinusoidal endothelial cells (LSEC) in HbS clearance and liver injury in SCD was not previously established. Using real-time intravital (in vivo) imaging in mice liver as well as flow cytometric analysis, confocal imaging and biochemical analysis of primary human LSEC, we show that liver injury in SCD is associated with accumulation of HbS in the LSEC, leading to senescence of these cells. Hepatic monocytes were observed to attenuate LSEC senescence by accelerating HbS clearance in the liver of SCD mice; however, this protection was impaired in P-selectin-deficient SCD mice secondary to reduced monocyte recruitment in the liver. These findings are the first to suggest that LSEC contribute to HbS clearance and HbS-induced LSEC senescence promotes progressive liver injury in SCD mice. Our results provide a novel insight into the pathogenesis of hemolysis-induced chronic liver injury in SCD caused by LSEC senescence. Identifying the regulators of LSEC-mediated HbS clearance may lead to new therapies to prevent the progression of liver injury in SCD.

Sundd:CSL Behring Inc:: Research Funding; Novartis AG: Research Funding; IHP Therapeutics: Research Funding.