Interleukin‐1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet‐mediated erythrocyte sickling

Autor: Jessica Venugopal, Jintao Wang, Chiao Guo, Daniel T. Eitzman
Rok vydání: 2021
Předmět:
Zdroj: British Journal of Haematology. 196:1040-1051
ISSN: 1365-2141
0007-1048
DOI: 10.1111/bjh.17941
Popis: Sickle cell disease (SCD) is associated with haemolytic anaemia and secondary activation of leucocytes and platelets, which in turn may further exacerbate haemolysis. As cytokine signalling pathways may participate in this cycle, the present study investigated whether pharmacological blockade of the interleukin-1 receptor (IL-1R) would mitigate anaemia in a murine model of SCD. Within 2 weeks of treatment, reduced markers of haemolysis were observed in anakinra-treated mice compared to vehicle-treated mice. After 4 weeks of anakinra treatment, mice showed increased numbers of erythrocytes, haemoglobin, and haematocrit, along with reduced reticulocytes. Blood from anakinra-treated mice was less susceptible to ex vivo erythrocyte sickling and was resistant to exogenous IL-1β-mediated sickling. Supernatant generated from IL-1β-treated platelets was sufficient to promote erythrocyte sickling, an effect not observed with platelet supernatant generated from IL-1R-/- mice. The sickling effect of IL-1β-treated platelet supernatant was inhibited by a transforming growth factor-β (TGF-β) neutralising antibody, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, and superoxide scavengers, but replicated by recombinant TGF-β. In conclusion, pharmacological IL-1R antagonism leads to improved anaemia in a murine SCD model. IL-1β stimulation of platelets promotes erythrocyte sickling. This effect may be mediated by platelet-derived TGF-β-induced reactive oxygen species generation though erythrocyte NADPH oxidase.
Databáze: OpenAIRE
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