Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway
Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Throu...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-05-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824001166 |
| _version_ | 1797213448866627584 |
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| author | Minhao Yu Yuan Shi Yuan Gao Yang Luo Yihua Jin Xiaoyi Liang Zhuoran Tao Guojun Zhu Haiping Lin Hao Li Jun Qin Zhijun Cao Ming Zhong |
| author_facet | Minhao Yu Yuan Shi Yuan Gao Yang Luo Yihua Jin Xiaoyi Liang Zhuoran Tao Guojun Zhu Haiping Lin Hao Li Jun Qin Zhijun Cao Ming Zhong |
| author_sort | Minhao Yu |
| collection | DOAJ |
| description | Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1β⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn’s disease. |
| first_indexed | 2024-04-24T10:58:27Z |
| format | Article |
| id | doaj.art-5afee8dc5a4e4a10bb2a3c49cff27946 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-04-24T10:58:27Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-5afee8dc5a4e4a10bb2a3c49cff279462024-04-12T04:44:22ZengElsevierPharmacological Research1096-11862024-05-01203107172Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathwayMinhao Yu0Yuan Shi1Yuan Gao2Yang Luo3Yihua Jin4Xiaoyi Liang5Zhuoran Tao6Guojun Zhu7Haiping Lin8Hao Li9Jun Qin10Zhijun Cao11Ming Zhong12Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, ChinaDepartment of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Corresponding authors.Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases;Renji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, 200127, China; Corresponding authors.Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Correspondence to: Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China.Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1β⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn’s disease.http://www.sciencedirect.com/science/article/pii/S1043661824001166AQP9Anti-TNF therapyCrohn's disease |
| spellingShingle | Minhao Yu Yuan Shi Yuan Gao Yang Luo Yihua Jin Xiaoyi Liang Zhuoran Tao Guojun Zhu Haiping Lin Hao Li Jun Qin Zhijun Cao Ming Zhong Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway Pharmacological Research AQP9 Anti-TNF therapy Crohn's disease |
| title | Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway |
| title_full | Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway |
| title_fullStr | Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway |
| title_full_unstemmed | Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway |
| title_short | Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway |
| title_sort | targeting aqp9 enhanced the anti tnf therapy response in crohn s disease by inhibiting lpa hippo pathway |
| topic | AQP9 Anti-TNF therapy Crohn's disease |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824001166 |
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