{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:10:51Z","timestamp":1793833851135,"version":"4.6.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/18\/46\/33817"],"award-info":[{"award-number":["PG\/18\/46\/33817"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n The aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We generated\n Nlrp3<\/jats:italic>\n A350V\/+<\/jats:sup>\n \/\n Gp1ba-<\/jats:italic>\n Cre\n KI\/+<\/jats:sup>\n mice carrying a mutation genetically similar to the one observed in human Muckle\u2013Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Platelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome.\n Nlrp3<\/jats:italic>\n A350V\/+<\/jats:sup>\n \/\n Gp1ba-<\/jats:italic>\n Cre\n KI\/+<\/jats:sup>\n 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.\n Nlrp3<\/jats:italic>\n A350V\/+<\/jats:sup>\n \/\n Gp1ba-<\/jats:italic>\n Cre\n KI\/+<\/jats:sup>\n mice had mild anemia, reduced Ter119\n +<\/jats:sup>\n cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-\u03b21 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in\n Nlrp3<\/jats:italic>\n A350V\/+<\/jats:sup>\n \/\n Gp1ba-<\/jats:italic>\n Cre\n KI\/+<\/jats:sup>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n MK\/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2023.1226196","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T04:24:12Z","timestamp":1691555052000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Joshua H.","family":"Bourne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie J.","family":"Hopkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine","family":"Whitworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Palis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yotis A.","family":"Senis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Rayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asif J.","family":"Iqbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Brill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-05-504449","article-title":"Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation","volume":"122","author":"Hottz","year":"2013","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018021709","article-title":"The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1\/TLR4 and Bruton tyrosine kinase","volume":"2","author":"Vogel","year":"2018","journal-title":"Blood Adv"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.705325","article-title":"Activation of platelet NLRP3 inflammasome in Crohn's disease","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Pharmacol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"791","DOI":"10.2147\/IJGM.S275481","article-title":"Expression and clinical prognostic value of platelet NLRP3 in acute coronary syndrome","volume":"13","author":"Peng","year":"2020","journal-title":"Int J Gen Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003377","article-title":"Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice","volume":"5","author":"Campos","year":"2021","journal-title":"Blood Adv"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201604-0892OC","article-title":"NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B(4) Synthesis","volume":"196","author":"Lee","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601745","article-title":"Deletion of Nlrp3 augments survival during polymicrobial sepsis by decreasing autophagy and enhancing phagocytosis","volume":"198","author":"Jin","year":"2017","journal-title":"J Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature04515","article-title":"Cryopyrin activates the inflammasome in response to toxins and ATP","volume":"440","author":"Mariathasan","year":"2006","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-09-877787","article-title":"The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions","volume":"133","author":"Nagy","year":"2019","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1055\/a-1896-6992","article-title":"CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear","volume":"122","author":"Bourne","year":"2022","journal-title":"Thromb Haemost"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3791\/56697","article-title":"Stenosis of the inferior vena cava: A murine model of deep vein thrombosis","author":"Payne","year":"2017","journal-title":"J Vis Exp"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-287623","article-title":"von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models","volume":"117","author":"Brill","year":"2011","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/09537104.2020.1797323","article-title":"Isolation of murine bone marrow by centrifugation or flushing for the analysis of hematopoietic cells - a comparative study","volume":"32","author":"Heibi","year":"2021","journal-title":"Platelets"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1055\/s-0041-1731288","article-title":"Rapid release of interleukin-1beta from human platelets is independent of NLRP3 and caspase","volume":"122","author":"Pennings","year":"2022","journal-title":"Thromb Haemost"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14073","article-title":"NLRP3 inflammasome activation in platelets in response to sepsis","volume":"7","author":"Cornelius","year":"2019","journal-title":"Physiol Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40164-015-0024-z","article-title":"GATA family transcriptional factors: emerging suspects in hematologic disorders","volume":"4","author":"Gao","year":"2015","journal-title":"Exp Hematol Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003276","article-title":"Megakaryocyte TGFbeta1 partitions erythropoiesis into immature progenitor\/stem cells and maturing precursors","volume":"136","author":"Di Giandomenico","year":"2020","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01463-3","article-title":"The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-beta","volume":"36","author":"Tanabe","year":"2022","journal-title":"Leukemia"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009302","article-title":"Don't you forget about me(gakaryocytes)","volume":"139","author":"Tilburg","year":"2022","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.exphem.2020.07.011","article-title":"Stress erythropoiesis: definitions and models for its study","volume":"89","author":"Paulson","year":"2020","journal-title":"Exp Hematol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.12.161","article-title":"The NLRP3 inflammasome and bruton's tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation","volume":"483","author":"Murthy","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112322","article-title":"Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo","volume":"209","author":"von Bruhl","year":"2012","journal-title":"J Exp Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1997.273.1.R400","article-title":"Physiological and cytokine responses in IL-1 beta-deficient mice after zymosan-induced inflammation","author":"Fantuzzi","year":"1997","journal-title":"Am J Physiol 273(1 Pt"},{"key":"B24","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12974-019-1452-1","article-title":"Interleukin-10 inhibits interleukin-1beta production and inflammasome activation of microglia in epileptic seizures","volume":"16","author":"Sun","year":"2019","journal-title":"J Neuroinflamm"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V87.10.4143.bloodjournal87104143","article-title":"Interleukin-1 beta induces production of granulocyte colony-stimulating factor in human hepatoma cells","volume":"87","author":"Lai","year":"1996","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154226","article-title":"GM-CSF suppresses antioxidant signaling and drives IL-1beta secretion through NRF2 downregulation","volume":"23","author":"Di Carlo","year":"2022","journal-title":"EMBO Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.exphem.2014.03.009","article-title":"Mobilization with granulocyte colony-stimulating factor blocks medullar erythropoiesis by depleting F4\/80(+)VCAM1(+)CD169(+)ER-HR3(+)Ly6G(+) erythroid island macrophages in the mouse","volume":"42","author":"Jacobsen","year":"2014","journal-title":"Exp Hematol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00067-11","article-title":"Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection","volume":"79","author":"Balamayooran","year":"2011","journal-title":"Infect Immun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01621","article-title":"Absence of the non-signalling chemerin receptor CCRL2 exacerbates acute inflammatory responses in vivo","volume":"8","author":"Regan-Komito","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.3105cm1","article-title":"Interleukin-1 (IL-1) pathway","volume":"3","author":"Weber","year":"2010","journal-title":"Sci Signal"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.119","article-title":"Regulation and function of the caspase-1 in an inflammatory microenvironment","volume":"135","author":"Lee","year":"2015","journal-title":"J Invest Dermatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021011045","article-title":"Ineffective erythropoiesis and its treatment","volume":"139","author":"Cazzola","year":"2022","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.160","article-title":"Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women","volume":"53","author":"Sherman","year":"2013","journal-title":"J Clin Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.08.027","article-title":"NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells","volume":"37","author":"Masters","year":"2012","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3346","article-title":"Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal","volume":"18","author":"Pietras","year":"2016","journal-title":"Nat Cell Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2020.01.001","article-title":"Interleukin-1beta inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche","volume":"22","author":"Wang","year":"2020","journal-title":"Cytotherapy"},{"key":"B37","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V79.8.1987.1987","article-title":"Effect of inflammatory cytokines on hypoxia-induced erythropoietin production","volume":"79","author":"Faquin","year":"1992","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2300065","article-title":"IL-18 binding protein-producing cells attenuate anemia in murine macrophage activation syndrome","volume":"210","author":"Harel","year":"2023","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.015","article-title":"Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets","volume":"122","author":"Denis","year":"2005","journal-title":"Cell"},{"key":"B40","article-title":"MegakaryocyteNLRP3 hyperactivation induces anemia and potentiates inflammatory response in mice. Research Square [Preprint]","author":"Brill","year":"2023"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1226196\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T04:24:18Z","timestamp":1691555058000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1226196\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,9]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2023.1226196"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1226196","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,9]]},"article-number":"1226196"}}