The RNA m^(6)A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression  

作　　者：Yang Liu Renjie Song Zhike Lu Lu Zhao Xinyi Zhan Yini Li Xuetao Cao 

机构地区：[1]Department of Immunology,Center for Immunotherapy,Institute of Basic Medical Sciences,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing,China [2]Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences,Suzhou,China [3]Frontier Research Center for Cell Response,Institute of Immunology,College of Life Sciences,Nankai University,Tianjin,China [4]School of Life Sciences,Westlake University,Hangzhou,China

出　　处：《Cellular & Molecular Immunology》2024年第1期6-18,共13页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(82322028 and 82071793);the Natural Science Foundation of Beijing Municipality(7212069);the Beijing Nova Program(20220484065)and the Young Elite Scientists Sponsorship Program by CAST(2019-2021QNRC001);supported by the National Natural Science Foundation of China(82388201);the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-017).

摘　　要：Emergency granulopoiesis and neutrophil mobilization that can be triggered by granulocyte colony-stimulating factor(G-CSF)through its receptor G-CSFR are essential for antibacterial innate defense.However,the epigenetic modifiers crucial for intrinsically regulating G-CSFR expression and the antibacterial response of neutrophils remain largely unclear.N6-methyladenosine(m^(6)A)RNA modification and the related demethylase alkB homolog 5(ALKBH5)are key epigenetic regulators of immunity and inflammation,but their roles in neutrophil production and mobilization are still unknown.We used cecal ligation and puncture(CLP)-induced polymicrobial sepsis to model systemic bacterial infection,and we report that ALKBH5 is required for emergency granulopoiesis and neutrophil mobilization.ALKBH5 depletion significantly impaired the production of immature neutrophils in the bone marrow of septic mice.In addition,Alkbh5-deficient septic mice exhibited higher retention of mature neutrophils in the bone marrow and defective neutrophil release into the circulation,which led to fewer neutrophils at the infection site than in their wild-type littermates.During bacterial infection,ALKBH5 imprinted production-and mobilization-promoting transcriptome signatures in both mouse and human neutrophils.Mechanistically,ALKBH5 erased m^(6)A methylation on the CSF3R mRNA to increase the mRNA stability and protein expression of G-CSFR,consequently upregulating cell surface G-CSFR expression and downstream STAT3 signaling in neutrophils.The RIP-qPCR results confirmed the direct binding of ALKBH5 to the CSF3R mRNA,and the binding strength declined upon bacterial infection,accounting for the decrease in G-CSFR expression on bacteria-infected neutrophils.Considering these results collectively,we define a new role of ALKBH5 in intrinsically driving neutrophil production and mobilization through m^(6)A demethylation-dependent posttranscriptional regulation,indicating that m^(6)A RNA modification in neutrophils is a potential target for treating bacteria

关 键 词：Emergency granulopoiesis Neutrophil mobilization ALKBH5 m^(6)A RNA modification G-CSF receptor 

分 类 号：R392[医药卫生—免疫学]