Reduced intracellular antioxidant capacity in platelets contributes to primary immune thrombocytopenia via ROS-NLRP3-caspase-1 pathway

Abstract

Primary immune thrombocytopenia (ITP) is a common acquired autoimmune hemorrhagic disease characterized by a low platelet count and increased risk of bleeding. However, some patients do not respond well to current therapeutic approaches. Further studies on pathogenesis and pathophysiology of ITP are needed to discover new therapeutic targets. We explored the role of enhanced intracellular oxidative stress and NLRP3 inflammasome activation of platelets in ITP. The expression of NLRP3 inflammasome was assessed in platelets from active ITP patients and healthy donors. Both the mRNA and protein expression level of platelet NLRP3 inflammasome was upregulated in ITP patients compared with healthy donors. Besides, the elevated caspase-1 activity and increased co-localization of NLRP3 and its adaptor molecule ASC indicated activation of NLRP3 inflammasome in ITP platelets. Significantly decreased intracellular antioxidant capacity was observed in ITP platelets. H2O2 supplementation elevated the expression of NLRP3 inflammasome and increased IL-1β secretion in ITP platelets. Preincubating ITP platelets with NAC down-regulated the expression of NLRP3 inflammasome. Pretreating ITP platelets with NLRP3 inhibitor MCC950 or caspase-1 inhibitor Z-YVAD-FMK significantly reduced the proportion of pyroptotic cells in H2O2-treated ITP platelets and suppressed IL-1β secretion in supernatants. Hence, platelet NLRP3 inflammasome activation resulted from reduced intracellular antioxidant capacity plays a critical role in ITP and might have potential diagnostic or therapeutic implications.