Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury
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Published:2023-12-19
Issue:1
Volume:10
Page:
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ISSN:2054-9369
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Container-title:Military Medical Research
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language:en
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Short-container-title:Military Med Res
Author:
Du Chang-Hong, Wu Yi-Ding, Yang Ke, Liao Wei-Nian, Ran Li, Liu Chao-Nan, Zhang Shu-Zhen, Yu Kuan, Chen Jun, Quan Yong, Chen Mo, Shen Ming-Qiang, Tang Hong, Chen Shi-Lei, Wang Song, Zhao Jing-Hong, Cheng Tian-Min, Wang Jun-PingORCID
Abstract
Abstract
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.
Funder
Key Program of the National Natural Science Foundation of China National Science Fund for Distinguished Young Scholars National Natural Science Foundation of China Chongqing Science and Technology Foundation Chongqing Science and Technology Commission
Publisher
Springer Science and Business Media LLC
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