PDF(Pubmed)
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.
摘要：
红白血病属于急性髓系白血病（AML）6型（M6），由于疾病预后不良，治疗仍然困难。Friend病毒（FV）是两种病毒的复合物：Friend鼠白血病病毒（F-MuLV）株以及有缺陷的脾病灶形成病毒（SFFV），可诱发小鼠急性红白血病。我们先前报道过迷走神经α7烟碱乙酰胆碱受体(nAChR)信号的激活促进HIV-1转录。迷走神经毒蕈碱信号是否介导FV诱导的红白血病及其潜在机制尚不清楚。在这项研究中,假手术和阴道切除的小鼠腹膜内注射FV。FV感染导致假小鼠贫血，迷走神经切断术逆转了这种变化。FV感染增加红细胞ProE，EryA,和脾脏中的EryB细胞，这些变化被迷走神经切断术阻断。在骨髓中，FV感染减少假小鼠的EryC细胞，迷走神经切断术抵消了这种效果。FV感染增加了脾CD4+和CD8+T细胞中胆碱乙酰转移酶（ChAT）的表达，迷走神经切断术逆转了这种变化。此外，在CD4+T细胞中ChAT缺失后,FV感染的野生型小鼠脾脏中EryA和EryB细胞的增加被逆转。在骨髓中，FV感染减少了假手术小鼠的EryB和EryC细胞,而CD4+T细胞中缺乏ChAT并不影响这种变化。氯氮平N-氧化物（CNO）对毒蕈碱乙酰胆碱受体4（mAChR4）的激活显着增加了脾脏中的EryB，但减少了FV感染小鼠骨髓中的EryC细胞群。因此，脾和骨髓中迷走神经mAChR4信号协同促进急性红白血病的发病机制。我们揭示了红白血病中神经调节的一种未被识别的机制。
