m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration
Abstract Neutrophil migration into the site of infection is necessary for antibacterial innate defense, whereas impaired neutrophil migration may result in excessive inflammation and even sepsis. The neutrophil migration directed by extracellular signals such as chemokines has been extensively studi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01020-z |
| _version_ | 1818234926873444352 |
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| author | Yang Liu Renjie Song Lu Zhao Zhike Lu Yini Li Xinyi Zhan Fengjiao Lu Jiang Yang Yamei Niu Xuetao Cao |
| author_facet | Yang Liu Renjie Song Lu Zhao Zhike Lu Yini Li Xinyi Zhan Fengjiao Lu Jiang Yang Yamei Niu Xuetao Cao |
| author_sort | Yang Liu |
| collection | DOAJ |
| description | Abstract Neutrophil migration into the site of infection is necessary for antibacterial innate defense, whereas impaired neutrophil migration may result in excessive inflammation and even sepsis. The neutrophil migration directed by extracellular signals such as chemokines has been extensively studied, yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation. N 6 -methyladenosine (m6A) RNA modification is important in immunity and inflammation, and our preliminary data indicate downregulation of RNA m6A demethylase alkB homolog 5 (ALKBH5) in neutrophils during bacterial infection. Whether m6A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain unknown. Here we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil migration. We found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture (CLP), and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil migration. Alkbh5-deficient neutrophils had lower CXCR2 expression, thus exhibiting impaired migration toward chemokine CXCL2. Mechanistically, ALKBH5-mediated m6A demethylation empowered neutrophils with high migration capability through altering the RNA decay, consequently regulating protein expression of its targets, neutrophil migration-related molecules, including increased expression of neutrophil migration-promoting CXCR2 and NLRP12, but decreased expression of neutrophil migration-suppressive PTGER4, TNC, and WNK1. Our findings reveal a previously unknown role of ALKBH5 in imprinting migration-promoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense, highlighting the potential application of targeting neutrophil m6A modification in controlling bacterial infections. |
| first_indexed | 2024-12-12T11:45:50Z |
| format | Article |
| id | doaj.art-bf2fb281bd7c4c6084b70755bf471c8b |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-12-12T11:45:50Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-bf2fb281bd7c4c6084b70755bf471c8b2022-12-22T00:25:27ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-06-017111510.1038/s41392-022-01020-zm6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migrationYang Liu0Renjie Song1Lu Zhao2Zhike Lu3Yini Li4Xinyi Zhan5Fengjiao Lu6Jiang Yang7Yamei Niu8Xuetao Cao9Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesSchool of Life Sciences, Westlake UniversitySchool of Life Sciences, Westlake UniversityDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Pathology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesDepartment of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical SciencesAbstract Neutrophil migration into the site of infection is necessary for antibacterial innate defense, whereas impaired neutrophil migration may result in excessive inflammation and even sepsis. The neutrophil migration directed by extracellular signals such as chemokines has been extensively studied, yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation. N 6 -methyladenosine (m6A) RNA modification is important in immunity and inflammation, and our preliminary data indicate downregulation of RNA m6A demethylase alkB homolog 5 (ALKBH5) in neutrophils during bacterial infection. Whether m6A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain unknown. Here we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil migration. We found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture (CLP), and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil migration. Alkbh5-deficient neutrophils had lower CXCR2 expression, thus exhibiting impaired migration toward chemokine CXCL2. Mechanistically, ALKBH5-mediated m6A demethylation empowered neutrophils with high migration capability through altering the RNA decay, consequently regulating protein expression of its targets, neutrophil migration-related molecules, including increased expression of neutrophil migration-promoting CXCR2 and NLRP12, but decreased expression of neutrophil migration-suppressive PTGER4, TNC, and WNK1. Our findings reveal a previously unknown role of ALKBH5 in imprinting migration-promoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense, highlighting the potential application of targeting neutrophil m6A modification in controlling bacterial infections.https://doi.org/10.1038/s41392-022-01020-z |
| spellingShingle | Yang Liu Renjie Song Lu Zhao Zhike Lu Yini Li Xinyi Zhan Fengjiao Lu Jiang Yang Yamei Niu Xuetao Cao m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration Signal Transduction and Targeted Therapy |
| title | m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| title_full | m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| title_fullStr | m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| title_full_unstemmed | m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| title_short | m6A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| title_sort | m6a demethylase alkbh5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration |
| url | https://doi.org/10.1038/s41392-022-01020-z |
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