Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases
Abstract Background Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhi...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02682-w |
| _version_ | 1797973544891580416 |
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| author | Chen Chen YuWei Zhou XinPeng Ning ShengLong Li DongDong Xue CaiLv Wei Zhu Zhu LongXiang Sheng BingZheng Lu Yuan Li XiaoYuan Ye YunZhao Fu Chuan Bai Wei Cai YuXuan Ding SuiZhen Lin GuangMei Yan YiJun Huang Wei Yin |
| author_facet | Chen Chen YuWei Zhou XinPeng Ning ShengLong Li DongDong Xue CaiLv Wei Zhu Zhu LongXiang Sheng BingZheng Lu Yuan Li XiaoYuan Ye YunZhao Fu Chuan Bai Wei Cai YuXuan Ding SuiZhen Lin GuangMei Yan YiJun Huang Wei Yin |
| author_sort | Chen Chen |
| collection | DOAJ |
| description | Abstract Background Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. Methods Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). Results Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. Conclusions Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic. |
| first_indexed | 2024-04-11T04:05:57Z |
| format | Article |
| id | doaj.art-186583cab01f48ae8a69a1cb6197adba |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T04:05:57Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-186583cab01f48ae8a69a1cb6197adba2023-01-01T12:23:35ZengBMCJournal of Neuroinflammation1742-20942022-12-0119111710.1186/s12974-022-02682-wDirectly targeting ASC by lonidamine alleviates inflammasome-driven diseasesChen Chen0YuWei Zhou1XinPeng Ning2ShengLong Li3DongDong Xue4CaiLv Wei5Zhu Zhu6LongXiang Sheng7BingZheng Lu8Yuan Li9XiaoYuan Ye10YunZhao Fu11Chuan Bai12Wei Cai13YuXuan Ding14SuiZhen Lin15GuangMei Yan16YiJun Huang17Wei Yin18Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen UniversityState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhou Cellprotek Pharmaceutical Co., Ltd.Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityAbstract Background Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. Methods Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). Results Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. Conclusions Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.https://doi.org/10.1186/s12974-022-02682-wASC inhibitorsInflammasomeLonidamineMultiple sclerosisIschemic strokeSepsis |
| spellingShingle | Chen Chen YuWei Zhou XinPeng Ning ShengLong Li DongDong Xue CaiLv Wei Zhu Zhu LongXiang Sheng BingZheng Lu Yuan Li XiaoYuan Ye YunZhao Fu Chuan Bai Wei Cai YuXuan Ding SuiZhen Lin GuangMei Yan YiJun Huang Wei Yin Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases Journal of Neuroinflammation ASC inhibitors Inflammasome Lonidamine Multiple sclerosis Ischemic stroke Sepsis |
| title | Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases |
| title_full | Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases |
| title_fullStr | Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases |
| title_full_unstemmed | Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases |
| title_short | Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases |
| title_sort | directly targeting asc by lonidamine alleviates inflammasome driven diseases |
| topic | ASC inhibitors Inflammasome Lonidamine Multiple sclerosis Ischemic stroke Sepsis |
| url | https://doi.org/10.1186/s12974-022-02682-w |
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