HbS promotes TLR4-mediated monocyte activation and proinflammatory cytokine production in sickle cell disease

Monocytes are considered crucial actors of inflammation in sickle cell disease (SCD), being responsible for an increased production of proinflammatory cytokines such as tumor necrosis factor a (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6. Although a role of free heme released by intravascular hemolysis has been suspected, the mechanisms underlying monocyte activation in patients with SCD remain unknown. Using purified human hemo-globin (Hb), we demonstrate herein, that cell-free HbS, unlike HbA or heme, is responsible for a major enhancement in the expression of proinflammatory cytokines by human monocytes. This effect was found mediated by direct interaction with the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex, resulting in the acti-vation of both the nuclear factor-KB (NF-KB) and type I interferon pathways. In Townes SCD mice, injection of HbS, unlike HbA, was responsible for an increased production of proinflammatory 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.

Automated summary

Monocyte activation and systemic inflammation in sickle cell disease (SCD) are associated with the interaction between hemoglobin S (HbS) and Toll-like receptor 4 (TLR4), resulting in the expression of proinflammatory cytokines through the NF-KB and type I interferon pathways. This finding provides new insights for therapeutic approaches targeting the HbS-TLR4 interaction in SCD.