Activation of Platelet Caspase-1 and P-Selectin Over-Expression in Sickle Cell Disease Patients: An Involvement of NLRP3 Inflammasome?

Sickle cell disease (SCD) is characterized by hemolytic anaemia, painful vaso-occlusive crises, and chronic inflammation resulting partly from platelet activation. It has been shown that platelets express the nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) and the apoptosis-associated speck-like protein containing a CARD (ASC), forming the NLRP3 inflammasome, which controls activation of caspase-1 and cleavage of interleukin-1β (IL-1β). Bruton tyrosine kinase (BTK), known to activate the NLRP3 inflammasome, is also expressed in platelets. In SCD, platelets are activated and can secrete increased quantities of IL-1β, suggesting a possible activation of the NLRP3 inflammasome. Here, we assessed platelet P-selectin expression, caspase-1 activation, platelet-neutrophil aggregate formations by flow cytometry and BTK phosphorylation by Western blot in a cohort of 81 adult SCD patients at steady state condition (34 SC and 47 SS patients). We showed an increase in platelet activation in sickle patients and a high level of platelet-neutrophil aggregate in SS patients compared to healthy subjects (17 AA). We also demonstrated platelet caspase-1 activation in SCD patients and obtained data suggesting for the first time NLRP3 inflammasome activation in SC patients. Further studies are needed to understand the mechanism of caspase-1 activation and evaluate the potential therapeutic efficiency of Ibrutinib, a BTK inhibitor.