Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy
Summary: Schlemm’s canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472400127X |
| _version_ | 1797291801698107392 |
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| author | Xinyu Gu Xun Chen Xuan Zhang Keli Liu Jing-Jing Li Wenyu Lv Lei Zeng Mingjuan Wu Weibin Zhou Weifa Wang Shunhua Shi Yicheng Deng Yunhua Li Xinbo Gao Rong Ju Alexandre Dubrac Xialin Liu Feng Zhang |
| author_facet | Xinyu Gu Xun Chen Xuan Zhang Keli Liu Jing-Jing Li Wenyu Lv Lei Zeng Mingjuan Wu Weibin Zhou Weifa Wang Shunhua Shi Yicheng Deng Yunhua Li Xinbo Gao Rong Ju Alexandre Dubrac Xialin Liu Feng Zhang |
| author_sort | Xinyu Gu |
| collection | DOAJ |
| description | Summary: Schlemm’s canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing SC development and functionality remains limited. Here, we show that vitronectin (VTN) produced by limbal macrophages promotes SC formation and prevents intraocular hypertension by activating integrin αvβ3 signaling. Genetic inactivation of this signaling system inhibited the phosphorylation of AKT and FOXO1 and reduced β-catenin activity and FOXC2 expression, thereby causing impaired Prox1 expression and deteriorated SC morphogenesis. This ultimately led to increased IOP and glaucomatous optic neuropathy. Intriguingly, we found that aged SC displayed downregulated integrin β3 in association with dampened Prox1 expression. Conversely, FOXO1 inhibition rejuvenated the aged SC by inducing Prox1 expression and SC regrowth, highlighting a possible strategy by targeting VTN/integrin αvβ3 signaling to improve SC functionality. |
| first_indexed | 2024-03-07T19:43:00Z |
| format | Article |
| id | doaj.art-edbae61332d34f9c8f8bc204615614a1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-07T19:43:00Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-edbae61332d34f9c8f8bc204615614a12024-02-29T05:19:00ZengElsevierCell Reports2211-12472024-02-01432113799Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathyXinyu Gu0Xun Chen1Xuan Zhang2Keli Liu3Jing-Jing Li4Wenyu Lv5Lei Zeng6Mingjuan Wu7Weibin Zhou8Weifa Wang9Shunhua Shi10Yicheng Deng11Yunhua Li12Xinbo Gao13Rong Ju14Alexandre Dubrac15Xialin Liu16Feng Zhang17State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaSun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaSun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaCentre de Recherche, CHU St. Justine, Montréal, QC, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, CanadaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China; Corresponding authorSummary: Schlemm’s canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing SC development and functionality remains limited. Here, we show that vitronectin (VTN) produced by limbal macrophages promotes SC formation and prevents intraocular hypertension by activating integrin αvβ3 signaling. Genetic inactivation of this signaling system inhibited the phosphorylation of AKT and FOXO1 and reduced β-catenin activity and FOXC2 expression, thereby causing impaired Prox1 expression and deteriorated SC morphogenesis. This ultimately led to increased IOP and glaucomatous optic neuropathy. Intriguingly, we found that aged SC displayed downregulated integrin β3 in association with dampened Prox1 expression. Conversely, FOXO1 inhibition rejuvenated the aged SC by inducing Prox1 expression and SC regrowth, highlighting a possible strategy by targeting VTN/integrin αvβ3 signaling to improve SC functionality.http://www.sciencedirect.com/science/article/pii/S221112472400127XCP: NeuroscienceCP: Cell biology |
| spellingShingle | Xinyu Gu Xun Chen Xuan Zhang Keli Liu Jing-Jing Li Wenyu Lv Lei Zeng Mingjuan Wu Weibin Zhou Weifa Wang Shunhua Shi Yicheng Deng Yunhua Li Xinbo Gao Rong Ju Alexandre Dubrac Xialin Liu Feng Zhang Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy Cell Reports CP: Neuroscience CP: Cell biology |
| title | Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| title_full | Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| title_fullStr | Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| title_full_unstemmed | Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| title_short | Macrophage-induced integrin signaling promotes Schlemm’s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| title_sort | macrophage induced integrin signaling promotes schlemm s canal formation to prevent intraocular hypertension and glaucomatous optic neuropathy |
| topic | CP: Neuroscience CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S221112472400127X |
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