Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation
Abstract Excessive uric acid (UA) is associated with age-related cataract. A previous study showed that a high UA level in the aqueous humor stimulated the senescence of lens epithelial cells (LECs), leading to cataract progression. To better understand the underlying mechanisms, we investigated UA-...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-01900-z |
| _version_ | 1797266913002258432 |
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| author | Hong Liang Lin Sheng Wang Kota Sato Yu Qiao Zhang Bei Ting He Jing Xu Toru Nakazawa Yong Jie Qin Hong Yang Zhang |
| author_facet | Hong Liang Lin Sheng Wang Kota Sato Yu Qiao Zhang Bei Ting He Jing Xu Toru Nakazawa Yong Jie Qin Hong Yang Zhang |
| author_sort | Hong Liang Lin |
| collection | DOAJ |
| description | Abstract Excessive uric acid (UA) is associated with age-related cataract. A previous study showed that a high UA level in the aqueous humor stimulated the senescence of lens epithelial cells (LECs), leading to cataract progression. To better understand the underlying mechanisms, we investigated UA-driven senescence in human lens tissue samples obtained during surgery, rat lens organ cultures, and in vivo experiments, using senescence-associated β-galactosidase (SA-β-gal) staining, electronic microscopy, Western blotting, and histological analyses. Initially, we identified markedly higher expressions of NLRP3 and caspase-1 in the lens capsules of hyper-uricemic patients compared to normo-uricemic patients. This increase was accompanied by a significant rise in the SA-β-gal positive rate. We next built a cataract model in which rat lenses in an organ culture system were treated with an increasing dosage of UA. Notably, opacification was apparent in the lenses treated with 800 μM of UA starting on the fifth day. Mechanistically, UA treatment not only significantly induced the expression of NLRP3, caspase-1, and IL-1β, but also upregulated the levels of SA-β-gal and the senescence regulators p53 and p21. These effects were fully reversed, and lens opacification was ameliorated by the addition of MCC950, a selective NLRP3 antagonist. Moreover, an in vivo model showed that intravitreal UA injection rapidly induced cataract phenotypes within 21 days, an effect significantly mitigated by co-injection with MCC950. Together, our findings suggest that targeting the UA-induced NLRP3 inflammasome with MCC950 could be a promising strategy for preventing cataract formation associated with inflammageing. |
| first_indexed | 2024-04-25T01:08:14Z |
| format | Article |
| id | doaj.art-78a1e7542c2e4b978e2ae04d3b407412 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-25T01:08:14Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-78a1e7542c2e4b978e2ae04d3b4074122024-03-10T12:05:58ZengNature Publishing GroupCell Death Discovery2058-77162024-03-0110111110.1038/s41420-024-01900-zUric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formationHong Liang Lin0Sheng Wang1Kota Sato2Yu Qiao Zhang3Bei Ting He4Jing Xu5Toru Nakazawa6Yong Jie Qin7Hong Yang Zhang8Department of Ophthalmology, Nanfang Hospital, Southern Medical UniversityDepartment of Ophthalmology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityDepartment of Ophthalmology, Tohoku University Graduate School of MedicineDepartment of Ophthalmology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityDepartment of Ophthalmology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityDepartment of Ophthalmology, Nanfang Hospital, Southern Medical UniversityDepartment of Ophthalmology, Tohoku University Graduate School of MedicineDepartment of Ophthalmology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityDepartment of Ophthalmology, Nanfang Hospital, Southern Medical UniversityAbstract Excessive uric acid (UA) is associated with age-related cataract. A previous study showed that a high UA level in the aqueous humor stimulated the senescence of lens epithelial cells (LECs), leading to cataract progression. To better understand the underlying mechanisms, we investigated UA-driven senescence in human lens tissue samples obtained during surgery, rat lens organ cultures, and in vivo experiments, using senescence-associated β-galactosidase (SA-β-gal) staining, electronic microscopy, Western blotting, and histological analyses. Initially, we identified markedly higher expressions of NLRP3 and caspase-1 in the lens capsules of hyper-uricemic patients compared to normo-uricemic patients. This increase was accompanied by a significant rise in the SA-β-gal positive rate. We next built a cataract model in which rat lenses in an organ culture system were treated with an increasing dosage of UA. Notably, opacification was apparent in the lenses treated with 800 μM of UA starting on the fifth day. Mechanistically, UA treatment not only significantly induced the expression of NLRP3, caspase-1, and IL-1β, but also upregulated the levels of SA-β-gal and the senescence regulators p53 and p21. These effects were fully reversed, and lens opacification was ameliorated by the addition of MCC950, a selective NLRP3 antagonist. Moreover, an in vivo model showed that intravitreal UA injection rapidly induced cataract phenotypes within 21 days, an effect significantly mitigated by co-injection with MCC950. Together, our findings suggest that targeting the UA-induced NLRP3 inflammasome with MCC950 could be a promising strategy for preventing cataract formation associated with inflammageing.https://doi.org/10.1038/s41420-024-01900-z |
| spellingShingle | Hong Liang Lin Sheng Wang Kota Sato Yu Qiao Zhang Bei Ting He Jing Xu Toru Nakazawa Yong Jie Qin Hong Yang Zhang Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation Cell Death Discovery |
| title | Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| title_full | Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| title_fullStr | Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| title_full_unstemmed | Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| title_short | Uric acid–driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| title_sort | uric acid driven nlrp3 inflammasome activation triggers lens epithelial cell senescence and cataract formation |
| url | https://doi.org/10.1038/s41420-024-01900-z |
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