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. Nlrp3A^350V/+/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.