Heme Oxygenase-1 Regulates the Hepatic Expression of Hemoglobin Scavenger Receptor CD163 in Sickle Cell Disease

Sickle cell disease (SCD) is the result of a genetic mutation in the β-globin gene, where both copies of the gene are affected. This mutation causes red blood cells to change shape into a sickle shape, leading to their premature destruction and the release of hemoglobin. Plasma haptoglobin scavenges cell free hemoglobin (Hb) and escorts it to the liver, where it is cleared by macrophages (specifically hepatic Kupffer cells) through a process that depends on the hemoglobin scavenger receptor CD163. Nevertheless, the persistent breakdown of red blood cells in SCD causes a decrease in plasma haptoglobin levels, which in turn leads to the buildup of hemoglobin, heme, and iron, leading to multi organ damage including liver damage. Past investigations have demonstrated a limited number of instances where there is a positive relationship between CD163 expression and unfavorable clinical outcomes in patients with SCD. However, the precise function and control of CD163 in regulating hepatobiliary damage in SCD have not yet been completely understood.

The objective of this study was to examine the function of CD163 as a potential biomarker for the severity of liver damage associated with SCD. This was done by utilizing a humanized mice model and liver biopsy samples obtained from SCD patients. We found that there is a positive correlation between chronic liver damage in mice and individuals with sickle cell disease (SCD) and increased levels of hepatic membrane bound CD163. Mechanistically we show that heme oxygenase 1 (HO-1) is a positive regulator of CD163 in the liver of SCD mice, independent of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling. Additional investigation revealed that toll-like receptors (TLRs) 4 and 9 interact with both CD163 and HO-1 and control the regulation of membrane bound CD163 in SCD mice liver. Finally, we demonstrate that the reduced activity of CD163 exacerbates liver damage caused by hemolysis in sickle cell disease (SCD) as a result of the accumulation of hemoglobin specifically in the liver.

This study finds CD163 as a possible indicator of liver damage caused by hemolysis in SCD. A comprehensive comprehension of the HO-1 mediated signaling pathways that regulate CD163 expression will prove valuable in the development of innovative treatment strategies for addressing tissue damage caused by hemolysis in SCD and other hemolytic diseases.

No relevant conflicts of interest to declare.