1. Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice.
- Author
-
Bourne, Joshua H., Campos, Joana, Hopkin, Sophie J., Whitworth, Katharine, Palis, James, Senis, Yotis A., Rayes, Julie, Iqbal, Asif J., and Brill, Alexander
- Subjects
NLRP3 protein ,BONE marrow cells ,ASCITIC fluids ,INFLAMMATION ,BLOOD platelet aggregation ,BLOOD platelet disorders ,PURE red cell aplasia - Abstract
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 Mrp3
A350V/+ /Gplba-CreKI/+ 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. Mrp3A350V/+ /Gplba-CreKI/+ 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. Nlrp3A350V/+ /Gplba-CreKI/+ 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 Nlrp3A350V/+ /Gplba-CreKI/+ 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. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF