{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:24:41Z","timestamp":1790677481502,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T00:00:00Z","timestamp":1580428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2017YFA0105800"],"award-info":[{"award-number":["2017YFA0105800"]}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670897"],"award-info":[{"award-number":["81670897"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Natural Science Funds for Distinguished Young Scholar","award":["2016A030306006"],"award-info":[{"award-number":["2016A030306006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL\/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-\/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-\u03b1, IL-1\u03b2, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4\u2013dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.<\/jats:p>","DOI":"10.3390\/biom10020210","type":"journal-article","created":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T11:55:56Z","timestamp":1580471756000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9103-9282","authenticated-orcid":false,"given":"Yunzhe","family":"Tian","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxing","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohao","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0506-6362","authenticated-orcid":false,"given":"Wenru","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 528400 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/iub.1358","article-title":"Cellular and molecular mechanisms of inflammation-induced angiogenesis","volume":"67","author":"Szade","year":"2015","journal-title":"IUBMB Life"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S0092-8674(00)80108-7","article-title":"Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis","volume":"86","author":"Hanahan","year":"1996","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1161\/CIRCULATIONAHA.105.535294","article-title":"Role of angiogenesis in cardiovascular disease: a critical appraisal","volume":"112","author":"Khurana","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s10456-015-9477-2","article-title":"The pathogenic role of angiogenesis in rheumatoid arthritis","volume":"18","author":"Elshabrawy","year":"2015","journal-title":"Angiogenesis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1350-9462(02)00043-5","article-title":"Vascular endothelial growth factors and angiogenesis in eye disease","volume":"22","author":"Witmer","year":"2003","journal-title":"Prog. 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