首页|Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury

Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury

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Background:The essential roles of platelets in thrombosis have been well recognized.Unexpectedly,thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological,physical and chemical origins,which could be suffered by military personnel and civilians during chemical,biological,radioactive,and nuclear events.Especially,thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia,while the underlying pathogenic mechanism remains elusive.Methods:A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation(IR).The phenotypic and functional changes of platelets and megakaryocytes(MKs)were determined by a comprehensive set of in vitro and in vivo assays,including flow cytometry,flow chamber,histopathology,Western blotting,and chromatin immunoprecipitation,in combination with transcriptomic analysis.The molecular mechanism was investigated both in vitro and in vivo,and was consolidated using MK-specific knockout mice.The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors.Results:In contrast to primitive MKs,mature MKs(mMKs)are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis.Interestingly,mMKs undergo minority mitochondrial outer membrane permeabilization(MOMP)post IR,resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes(cGAS-STING)pathway via the release of mitochondrial DNA.The subsequent interferon-β(IFN-β)response in mMKs upregulates a GTPase guanylate-binding protein 2(GBP2)to produce large and hyperreactive platelets that favor thrombosis.Further,we unmask that autophagy restrains minority MOMP in mMKs post IR.Conclusions:Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.

Radiation injuryThrombocytopeniaPlatelet sizePlatelet hyperreactivityMegakaryocytes(MKs)

Chang-Hong Du、Yi-Ding Wu、Ke Yang、Wei-Nian Liao、Li Ran、Chao-Nan Liu、Shu-Zhen Zhang、Kuan Yu、Jun Chen、Yong Quan、Mo Chen、Ming-Qiang Shen、Hong Tang、Shi-Lei Chen、Song Wang、Jing-Hong Zhao、Tian-Min Cheng、Jun-Ping Wang

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State Key Laboratory of Trauma,Burns and Combined Injury,Institute of Combined Injury,Chongqing Engineering Research Center for Nanomedicine,College of Preventive Medicine,Army Medical University,Chongqing 400038,China

Frontier Medical Training Brigade,Army Medical University,Hutubi 831200,Xinjiang,China

Department of Nephrology,the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing,Kidney Center of PLA,Xinqiao Hospital,Army Medical University,Chongqing 400037,China

2024

10.1186/s40779-023-00499-z

军事医学研究(英文)

军事医学研究(英文)

CSTPCD
ISSN：2095-7467
年,卷(期)：2024.11(6)