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...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 eryth-roleukemia in mice.We have previously reported that activation of vagalα7 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 coun-teracted by vagotomy.FV infection increased choline acetyltransferase(ChAT)expression in splenic CD4^(+)and CD8þT 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.展开更多
基金from National Natural Science Foundation of China(82241042,81970075,81730001,91942305)National Key Research and Development Program of China(2022YFC2304700)+1 种基金Science and Technology Commission of Shanghai Municipality(20DZ2261200)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210602).
文摘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 eryth-roleukemia in mice.We have previously reported that activation of vagalα7 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 coun-teracted by vagotomy.FV infection increased choline acetyltransferase(ChAT)expression in splenic CD4^(+)and CD8þT 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.