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

Abstract

BackgroundThe 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.ObjectiveThe aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.MethodsWe generated Nlrp3A350V/+/Gp1ba-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.ResultsPlatelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. Nlrp3A350V/+/Gp1ba-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/+/Gp1ba-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/+/Gp1ba-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.ConclusionMK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases

“…A variety of inflammasomes (NLRP3 [NOD-like receptor thermal protein domain associated protein 3], NLRP1, AIM2 [absent in melanoma 2] and NLRC4) have been linked to the development of cardiocerebrovascular diseases, and blocking these multiprotein complexes presents as a potential therapeutic target for disease regulation with only mild immunodeficiency side effects (Borborema et al, 2020;Deng et al, 2023;Shao et al, 2021). Among them, the NLRP3 inflammasome is a canonical inflammasome and has been extensively studied in cardio-cerebrovascular diseases owing to its relevance (Chen, Zhu, et al, 2023) among a cornucopia of DAMPs and PAMPs (Bourne et al, 2023;Chen, Lan, et al, 2023;M. Zhao, Zheng, et al, 2023).…”