Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma
Background: Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology....
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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/S2213231723004226 |
| _version_ | 1797300356915396608 |
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| author | Yanhong Wang Yanqing Le Jie Wu Wenqu Zhao Qian Zhang Guiling Xu Zhaoqian Gong Maosheng Xu Yanyan Ma Changhui Yu Shaoxi Cai Haijin Zhao |
| author_facet | Yanhong Wang Yanqing Le Jie Wu Wenqu Zhao Qian Zhang Guiling Xu Zhaoqian Gong Maosheng Xu Yanyan Ma Changhui Yu Shaoxi Cai Haijin Zhao |
| author_sort | Yanhong Wang |
| collection | DOAJ |
| description | Background: Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology. However, the altered metabolic signatures and the roles of metabolic to allergic airway inflammation remain unclear. Methods: Male C57BL/6 J mice were sensitized and challenged with toluene diisocyanate (TDI) to generate a chemically induced asthma model. Pulmonary untargeted metabolomics was employed. According to results, mice were orally administered allopurinol, a xanthine oxidase (XO) inhibitor. Human bronchial epithelial cells (16HBE) were stimulated by TDI-human serum albumin (HSA). Results: We identified the purine metabolism was the most enriched pathway in TDI-exposed lungs, corresponding to the increase of xanthine and uric acid, products of purine degradation mediated by XO. Inhibition of XO by allopurinol ameliorates TDI-induced oxidative stress and DNA damage, mixed granulocytic airway inflammation and Th1, Th2 and Th17 immunology as well as HMGB1 acetylation and secretion. Mechanistically, HMGB1 acetylation was caused by decreased activation of the NAD+-sirtuin 1 (SIRT1) axis triggered by hyperactivation of the DNA damage sensor poly (ADP-ribose)-polymerase 1 (PARP-1). This was rescued by allopurinol, PARP-1 inhibitor or supplementation with NAD+ precursor in a SIRT1-dependent manner. Meanwhile, allopurinol attenuated Nrf2 defect due to SIRT1 inactivation to help ROS scavenge. Conclusions: We demonstrated a novel regulation of HMGB1 acetylation and secretion by purine metabolism that is critical for asthma onset. Allopurinol may have therapeutic potential in patients with asthma. |
| first_indexed | 2024-03-07T23:06:00Z |
| format | Article |
| id | doaj.art-54141a55fc59437f8d9d0584a6a2dcde |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-07T23:06:00Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-54141a55fc59437f8d9d0584a6a2dcde2024-02-22T04:52:11ZengElsevierRedox Biology2213-23172024-04-0170103021Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthmaYanhong Wang0Yanqing Le1Jie Wu2Wenqu Zhao3Qian Zhang4Guiling Xu5Zhaoqian Gong6Maosheng Xu7Yanyan Ma8Changhui Yu9Shaoxi Cai10Haijin Zhao11Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaDepartment of Respiratory and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, ChinaChronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; Corresponding author. Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, No 1838, Guangzhou Da Dao Bei, Guangzhou, 510515, China.Background: Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology. However, the altered metabolic signatures and the roles of metabolic to allergic airway inflammation remain unclear. Methods: Male C57BL/6 J mice were sensitized and challenged with toluene diisocyanate (TDI) to generate a chemically induced asthma model. Pulmonary untargeted metabolomics was employed. According to results, mice were orally administered allopurinol, a xanthine oxidase (XO) inhibitor. Human bronchial epithelial cells (16HBE) were stimulated by TDI-human serum albumin (HSA). Results: We identified the purine metabolism was the most enriched pathway in TDI-exposed lungs, corresponding to the increase of xanthine and uric acid, products of purine degradation mediated by XO. Inhibition of XO by allopurinol ameliorates TDI-induced oxidative stress and DNA damage, mixed granulocytic airway inflammation and Th1, Th2 and Th17 immunology as well as HMGB1 acetylation and secretion. Mechanistically, HMGB1 acetylation was caused by decreased activation of the NAD+-sirtuin 1 (SIRT1) axis triggered by hyperactivation of the DNA damage sensor poly (ADP-ribose)-polymerase 1 (PARP-1). This was rescued by allopurinol, PARP-1 inhibitor or supplementation with NAD+ precursor in a SIRT1-dependent manner. Meanwhile, allopurinol attenuated Nrf2 defect due to SIRT1 inactivation to help ROS scavenge. Conclusions: We demonstrated a novel regulation of HMGB1 acetylation and secretion by purine metabolism that is critical for asthma onset. Allopurinol may have therapeutic potential in patients with asthma.http://www.sciencedirect.com/science/article/pii/S2213231723004226AllopurinolAsthmaHMGB1Purine metabolismSIRT1 |
| spellingShingle | Yanhong Wang Yanqing Le Jie Wu Wenqu Zhao Qian Zhang Guiling Xu Zhaoqian Gong Maosheng Xu Yanyan Ma Changhui Yu Shaoxi Cai Haijin Zhao Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma Redox Biology Allopurinol Asthma HMGB1 Purine metabolism SIRT1 |
| title | Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma |
| title_full | Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma |
| title_fullStr | Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma |
| title_full_unstemmed | Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma |
| title_short | Inhibition of xanthine oxidase by allopurinol suppresses HMGB1 secretion and ameliorates experimental asthma |
| title_sort | inhibition of xanthine oxidase by allopurinol suppresses hmgb1 secretion and ameliorates experimental asthma |
| topic | Allopurinol Asthma HMGB1 Purine metabolism SIRT1 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723004226 |
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