TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease
Abstract TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte tran...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53528-3 |
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| author | Menghao Zhang Na Kang Xin Yu Xiaoyang Zhang Qinghui Duan Xianqiang Ma Qiancheng Zhao Zhimian Wang Xiao’ou Wang Yeling Liu Yuxiao Zhang Can Zhu Ruiyu Gao Xin Min Cuifeng Li Jin Jin Qian Cao Rongbei Liu Xiaoyin Bai Hong Yang Lidan Zhao Jinjing Liu Hua Chen Yonghui Zhang Wanli Liu Wenjie Zheng |
| author_facet | Menghao Zhang Na Kang Xin Yu Xiaoyang Zhang Qinghui Duan Xianqiang Ma Qiancheng Zhao Zhimian Wang Xiao’ou Wang Yeling Liu Yuxiao Zhang Can Zhu Ruiyu Gao Xin Min Cuifeng Li Jin Jin Qian Cao Rongbei Liu Xiaoyin Bai Hong Yang Lidan Zhao Jinjing Liu Hua Chen Yonghui Zhang Wanli Liu Wenjie Zheng |
| author_sort | Menghao Zhang |
| collection | DOAJ |
| description | Abstract TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD. |
| format | Article |
| id | doaj-art-42f1187a7b074526b5f4815c854849db |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-42f1187a7b074526b5f4815c854849db2025-01-05T12:36:16ZengNature PortfolioNature Communications2041-17232024-10-0115111710.1038/s41467-024-53528-3TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s diseaseMenghao Zhang0Na Kang1Xin Yu2Xiaoyang Zhang3Qinghui Duan4Xianqiang Ma5Qiancheng Zhao6Zhimian Wang7Xiao’ou Wang8Yeling Liu9Yuxiao Zhang10Can Zhu11Ruiyu Gao12Xin Min13Cuifeng Li14Jin Jin15Qian Cao16Rongbei Liu17Xiaoyin Bai18Hong Yang19Lidan Zhao20Jinjing Liu21Hua Chen22Yonghui Zhang23Wanli Liu24Wenjie Zheng25Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversitySchool of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversitySchool of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityCenter for Neuroimmunology and Health Longevity, the Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of gastroenterology & Inflammatory bowel disease Center, Sir Run Run Shaw hospital, school of medicine, Zhejiang UniversityDepartment of gastroenterology & Inflammatory bowel disease Center, Sir Run Run Shaw hospital, school of medicine, Zhejiang UniversityDepartment of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratorySchool of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua UniversityState Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key LaboratoryAbstract TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.https://doi.org/10.1038/s41467-024-53528-3 |
| spellingShingle | Menghao Zhang Na Kang Xin Yu Xiaoyang Zhang Qinghui Duan Xianqiang Ma Qiancheng Zhao Zhimian Wang Xiao’ou Wang Yeling Liu Yuxiao Zhang Can Zhu Ruiyu Gao Xin Min Cuifeng Li Jin Jin Qian Cao Rongbei Liu Xiaoyin Bai Hong Yang Lidan Zhao Jinjing Liu Hua Chen Yonghui Zhang Wanli Liu Wenjie Zheng TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease Nature Communications |
| title | TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease |
| title_full | TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease |
| title_fullStr | TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease |
| title_full_unstemmed | TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease |
| title_short | TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease |
| title_sort | tnf inhibitors target a mevalonate metabolite trpm2 calcium signaling axis in neutrophils to dampen vasculitis in behcet s disease |
| url | https://doi.org/10.1038/s41467-024-53528-3 |
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