Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice

BACKGROUND: The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK) lineage remains elusive. OBJECTIVE: The aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets. METHODS: We generated Nlrp3 (A350V/+)/Gp1ba-Cre(KI/+) mice carrying a mutation genetically similar to the one observed in human Muckle–Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets. RESULTS: Platelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. Nlrp3 (A350V/+)/Gp1ba-Cre(KI/+) mice developed normally and had normal platelet counts. Expression of major platelet receptors, platelet aggregation, platelet deposition on collagen under shear, and deep vein thrombosis were unchanged. Nlrp3 (A350V/+)/Gp1ba-Cre(KI/+) mice had mild anemia, reduced Ter119(+) cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-β1 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in Nlrp3 (A350V/+)/Gp1ba-Cre(KI/+) mice induced increased neutrophil egression and elevated levels of a set of proinflammatory cytokines, alongside IL-10 and G-CSF, in the peritoneal fluid as compared with control animals. CONCLUSION: MK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.