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

•Hemoglobin S, unlike hemoglobin A or heme, is responsible for TLR4-mediated monocyte activation.•Interaction between hemoglobin S and the TLR4/MD-2 complex results in the activation of both the NF-κB and type I interferon pathways. [Display omitted] Monocytes are considered crucial actors of inflam...

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Published in:Blood 2022-11, Vol.140 (18), p.1972-1982
Main Authors: Allali, Slimane, Rignault-Bricard, Rachel, de Montalembert, Mariane, Taylor, Melissa, Bouceba, Tahar, Hermine, Olivier, Maciel, Thiago Trovati
Format: Article
Language:English
Subjects:
Anemia, Sickle Cell - metabolism
Animals
Cytokines - metabolism
Heme - metabolism
Humans
Inflammation - metabolism
Mice
Monocytes - metabolism
NF-kappa B - metabolism
Signal Transduction
Toll-Like Receptor 4 - metabolism
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Summary:•Hemoglobin S, unlike hemoglobin A or heme, is responsible for TLR4-mediated monocyte activation.•Interaction between hemoglobin S and the TLR4/MD-2 complex results in the activation of both the NF-κB and type I interferon pathways. [Display omitted] 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 α (TNF-α), interleukin-1β (IL-1β), 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 hemoglobin (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 activation of both the nuclear factor-κB (NF-κB) 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. Patients with sickle cell disease (SCD) have more inflammation than patients with other hemoglobinopathies associated with intravascular hemolysis. Allali and colleagues address this conundrum, demonstrating that free hemoglobin S (HbS) leads to substantially greater toll-like receptor 4 (TLR4)-mediated monocyte activation and inflammatory cytokine production than hemoglobin A, despite differing by only 1 amino acid. In vivo, free HbS activates both NF-κB and the type I interferon pathways, and this can be blocked by TLR4 inhibitors.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2021014894