Figure 3.

Mechanisms of protection against free heme. A range of extracellular mechanisms confer protection against cell-free Hb and heme. Under hemolytic conditions, Hb is released from RBC into the circulation where it is scavenged by Hp, thereby preventing Hb oxidation, and allowing for the uptake of Hb:Hp complexes via the CD163 receptor. Once the scavenging capacity of Hp is exhausted, Hb becomes oxidized, releasing its heme prosthetic groups. These can be scavenged by albumin, HDL and LDL, α1-microglobulin, acting as “scavenging buffer,” and ultimately by Hx, which has the highest affinity for free heme. Hx:heme complexes are taken up via the CD91 receptor, delivering heme for catabolism by HO-1. Intracellular heme, whether originating from the extra- or intracellular compartment, is degraded via HO-1. The labile Fe released from heme catabolism is subsequently scavenged by FtH, thus conferring cytoprotection against heme-Fe. Abbreviations: Fe, iron; FtH, ferritin; Hp, haptoglobin; Hb, hemoglobin; HDL/LDL, high/low-density lipoprotein; Hx, hemopexin; ROS, reactive oxygen species.