A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization
Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000351 |
| _version_ | 1797300394154524672 |
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| author | Chunlu Li Chengsi Deng Siwei Wang Xiang Dong Bing Dai Wendong Guo Qiqiang Guo Yanling Feng Hongde Xu Xiaoyu Song Liu Cao |
| author_facet | Chunlu Li Chengsi Deng Siwei Wang Xiang Dong Bing Dai Wendong Guo Qiqiang Guo Yanling Feng Hongde Xu Xiaoyu Song Liu Cao |
| author_sort | Chunlu Li |
| collection | DOAJ |
| description | Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity. |
| first_indexed | 2024-03-07T23:06:32Z |
| format | Article |
| id | doaj.art-e31641bdde144ff0ad5ddf695e922de1 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-07T23:06:32Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-e31641bdde144ff0ad5ddf695e922de12024-02-22T04:52:19ZengElsevierRedox Biology2213-23172024-04-0170103059A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarizationChunlu Li0Chengsi Deng1Siwei Wang2Xiang Dong3Bing Dai4Wendong Guo5Qiqiang Guo6Yanling Feng7Hongde Xu8Xiaoyu Song9Liu Cao10The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaDepartment of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, ChinaThe College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, China; Corresponding author. The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.http://www.sciencedirect.com/science/article/pii/S2213231724000351MacrophageROSChk2PKM2p21 |
| spellingShingle | Chunlu Li Chengsi Deng Siwei Wang Xiang Dong Bing Dai Wendong Guo Qiqiang Guo Yanling Feng Hongde Xu Xiaoyu Song Liu Cao A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization Redox Biology Macrophage ROS Chk2 PKM2 p21 |
| title | A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization |
| title_full | A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization |
| title_fullStr | A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization |
| title_full_unstemmed | A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization |
| title_short | A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization |
| title_sort | novel role for the ros atm chk2 axis mediated metabolic and cell cycle reprogramming in the m1 macrophage polarization |
| topic | Macrophage ROS Chk2 PKM2 p21 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000351 |
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