LAUSR

Monocytes are considered crucial actors of inflammation in sickle cell disease (SCD), being responsible for an increased production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Although a role of free heme released by intravascular hemolysis has been suspected, the mechanisms underlying monocyte activation in SCD patients remain unknown. Using purified human hemoglobin (Hb), we demonstrate herein, that cell-free HbS, unlike HbA or heme, is responsible for a major enhancement in the expression of pro-inflammatory cytokines by human monocytes. This effect was found mediated by direct interaction with the TLR4/MD-2 complex, resulting in an activation of both the NF-κB and the type I interferon pathways. In Townes SCD mice, injection of HbS, unlike HbA, was responsible for an increased production of pro-inflammatory cytokines, which was prevented by the TLR4 inhibitor TAK-242. Our results reveal a novel mechanism of monocyte activation and systemic inflammation in SCD, which opens new promising therapeutic perspectives targeting the HbS-TLR4 interaction.