Vagal-mAChR4 signaling promotes Friend virus complex (FV)-induced acute erythroleukemia

Shuting Song; Zhekai Lin; Caiqi Zhao; Jing Wen; Jie Chen; Shitao Xie; Huaxin Qi; Jianhua Wang; Xiao Su

doi:10.1016/j.virs.2023.05.005

June 2023

. doi: 10.1016/j.virs.2023.05.005

Citation: Shuting Song, Zhekai Lin, Caiqi Zhao, Jing Wen, Jie Chen, Shitao Xie, Huaxin Qi, Jianhua Wang, Xiao Su. Vagal-mAChR4 signaling promotes Friend virus complex (FV)-induced acute erythroleukemia .VIROLOGICA SINICA, 2023, 38(3) : 429-439. http://dx.doi.org/10.1016/j.virs.2023.05.005

迷走神经-M4型乙酰胆碱受体信号通路促进FV病毒复合物诱导的急性红白血病

宋姝庭 ^a,b,c ,
林哲锴 ^a,b,c ,
赵才琦 ^a,b,c ,
闻婧 ^a,b,c ,
陈杰 ^a,b,c ,
谢什韬 ^a,b,c ,
齐华新 ^a,b,c ,
王建华 ^d ,
苏枭 ^a,b,c,e,,

a. 中国科学院上海巴斯德研究所呼吸道感染与免疫课题组, 上海 200031;
b. 中国科学院上海巴斯德研究所中国科学院分子病毒学与免疫学重点实验室, 上海 200031;
c. 中国科学院大学, 北京, 101408;
d. 中国科学院广州生物医学与健康研究所, 广州 510530;
e. 肺组织炎症与损伤上海市重点实验室, 上海 200031

通讯作者： 苏枭, xsu@ips.ac.cn
收稿日期： 2022-07-04
录用日期： 2023-05-08

摘要

红白血病属于6型急性髓系白血病，由于该病预后较差，治疗仍较为困难。FV病毒（Friend virus，FV）是由小鼠白血病病毒（Friend murine leukemia virus，F-MuLV）株和脾脏集落病毒（Spleen focal forming virus，SFFV）两种病毒组成的复合体，可诱导小鼠发生急性红白血病。我们之前已经报道了迷走神经α7烟碱型乙酰胆碱受体（nAChR）信号通路的激活促进HIV-1转录。迷走神经毒蕈碱信号通路是否介导FV诱导的红白血病及其潜在机制尚不清楚。在本研究中，分别对假手术和迷走神经切除小鼠腹腔注射FV。FV感染引起假手术小鼠贫血，迷走神经切断术可逆转这一变化。FV感染增加了脾脏中幼红细胞ProE、EryA和EryB细胞的数量，这些变化可被迷走神经切断术阻断。在骨髓中，FV感染减少了假手术小鼠的EryC细胞，这一作用可被迷走神经切断术所抵消。FV感染增加了脾脏CD4⁺和CD8⁺ T细胞中胆碱乙酰转移酶（ChAT）的表达，迷走神经切断术可逆转这一变化。此外，在CD4⁺ T细胞中敲除ChAT后，FV感染野生型小鼠脾脏中增加的EryA和EryB细胞被逆转。在骨髓中，FV感染减少了假手术小鼠的EryB和EryC细胞，而在CD4⁺ T细胞中缺乏ChAT并不影响这种变化。氯氮平N-氧化物（CNO）激活毒蕈碱型乙酰胆碱受体4（mAChR4）显著增加FV感染小鼠脾脏中的EryB，但减少骨髓中的EryC细胞群。因此，脾脏和骨髓中的迷走神经-mAChR4信号通路协同促进急性红白血病的发病。我们揭示了红白血病发生和发展中的神经调节机制。
- FV病毒
- , 急性红白血病
- , 幼红细胞
- , 胆碱乙酰转移酶

Vagal-mAChR4 signaling promotes Friend virus complex (FV)-induced acute erythroleukemia

Shuting Song ^a,b,c ,
Zhekai Lin ^a,b,c ,
Caiqi Zhao ^a,b,c ,
Jing Wen ^a,b,c ,
Jie Chen ^a,b,c ,
Shitao Xie ^a,b,c ,
Huaxin Qi ^a,b,c ,
Jianhua Wang ^d ,
Xiao Su ^a,b,c,e,,

a. Unit of Respiratory Infection and Immunity, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China;
b. CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China;
c. University of Chinese Academy of Sciences, Beijing, 101408, China;
d. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China;
e. Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, 200031, China

Corresponding author: Xiao Su, xsu@ips.ac.cn
Received Date: 04 July 2022
Accepted Date: 08 May 2023

Abstract

Erythroleukemia belongs to acute myeloid leukemia (AML) type 6 (M6), and treatment remains difficult due to the poor prognosis of the disease. Friend virus (FV) is a complex of two viruses: Friend murine leukemia virus (F-MuLV) strain along with a defective spleen focus-forming virus (SFFV), which can induce acute erythroleukemia in mice. We have previously reported that activation of vagal α7 nicotinic acetylcholine receptor (nAChR) signaling promotes HIV-1 transcription. Whether vagal muscarinic signaling mediates FV-induced erythroleukemia and the underlying mechanisms remain unclear. In this study, sham and vagotomized mice were intraperitoneally injected with FV. FV infection caused anemia in sham mice, and vagotomy reversed this change. FV infection increased erythroblasts ProE, EryA, and EryB cells in the spleen, and these changes were blocked by vagotomy. In bone marrow, FV infection reduced EryC cells in sham mice, an effect that was counteracted by vagotomy. FV infection increased choline acetyltransferase (ChAT) expression in splenic CD4⁺ and CD8⁺ T cells, and this change was reversed by vagotomy. Furthermore, the increase of EryA and EryB cells in spleen of FV-infected wild-type mice was reversed after deletion of ChAT in CD4⁺ T cells. In bone marrow, FV infection reduced EryB and EryC cells in sham mice, whereas lack of ChAT in CD4⁺ T cells did not affect this change. Activation of muscarinic acetylcholine receptor 4 (mAChR4) by clozapine N-oxide (CNO) significantly increased EryB in the spleen but decreased the EryC cell population in the bone marrow of FV-infected mice. Thus, vagal-mAChR4 signaling in the spleen and bone marrow synergistically promotes the pathogenesis of acute erythroleukemia. We uncover an unrecognized mechanism of neuromodulation in erythroleukemia.
- Vagus nerve
- , Friend virus (FV)
- , Acute erythroleukemia
- , Erythroblast
- , Choline acetyltransferase (ChAT)

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