c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses
Abstract B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-04-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-00948-6 |
| _version_ | 1797247019203428352 |
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| author | Xu-Yan Wang Yuan Wei Bo Hu Yuan Liao Xiaodong Wang Wen-Hua Wan Chun-Xiang Huang Mahepali Mahabati Zheng-Yu Liu Jing-Rui Qu Xiao-Dan Chen Dong-Ping Chen Dong-Ming Kuang Xue-Hao Wang Yun Chen |
| author_facet | Xu-Yan Wang Yuan Wei Bo Hu Yuan Liao Xiaodong Wang Wen-Hua Wan Chun-Xiang Huang Mahepali Mahabati Zheng-Yu Liu Jing-Rui Qu Xiao-Dan Chen Dong-Ping Chen Dong-Ming Kuang Xue-Hao Wang Yun Chen |
| author_sort | Xu-Yan Wang |
| collection | DOAJ |
| description | Abstract B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27−CD38−CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells. |
| first_indexed | 2024-04-24T19:52:02Z |
| format | Article |
| id | doaj.art-b787fe1fbe744e1b887a5d20f70d0ea7 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-24T19:52:02Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-b787fe1fbe744e1b887a5d20f70d0ea72024-03-24T12:35:11ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-04-017111110.1038/s41392-022-00948-6c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responsesXu-Yan Wang0Yuan Wei1Bo Hu2Yuan Liao3Xiaodong Wang4Wen-Hua Wan5Chun-Xiang Huang6Mahepali Mahabati7Zheng-Yu Liu8Jing-Rui Qu9Xiao-Dan Chen10Dong-Ping Chen11Dong-Ming Kuang12Xue-Hao Wang13Yun Chen14MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityDepartment of Laboratory Medicine, the Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Laboratory Medicine, the Third Affiliated Hospital of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences, Shenzhen University Health Science CenterMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen UniversityHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical UniversityAbstract B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27−CD38−CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells.https://doi.org/10.1038/s41392-022-00948-6 |
| spellingShingle | Xu-Yan Wang Yuan Wei Bo Hu Yuan Liao Xiaodong Wang Wen-Hua Wan Chun-Xiang Huang Mahepali Mahabati Zheng-Yu Liu Jing-Rui Qu Xiao-Dan Chen Dong-Ping Chen Dong-Ming Kuang Xue-Hao Wang Yun Chen c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses Signal Transduction and Targeted Therapy |
| title | c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses |
| title_full | c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses |
| title_fullStr | c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses |
| title_full_unstemmed | c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses |
| title_short | c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses |
| title_sort | c myc driven glycolysis polarizes functional regulatory b cells that trigger pathogenic inflammatory responses |
| url | https://doi.org/10.1038/s41392-022-00948-6 |
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