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Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation\/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1\u03b2 expression and RGC death via a caspase-1\u2013dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)\/NLRP3 inflammasomes and a caspase-1\u2013independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1\u03b2 production and RGC death and highlight signal transduction in a caspase-1\u2013dependent NLRP1\/NLRP3 inflammasome pathway and a caspase-1\u2013independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.<\/jats:p>","DOI":"10.1073\/pnas.1402819111","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T01:15:59Z","timestamp":1405386959000},"page":"11181-11186","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":277,"title":["Caspase-8 promotes NLRP1\/NLRP3 inflammasome activation and IL-1\u03b2 production in acute glaucoma"],"prefix":"10.1073","volume":"111","author":[{"given":"Wei","family":"Chi","sequence":"first","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Chen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandong","family":"Wang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingting","family":"Zhu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ge","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Weinreb","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehong","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2014,7,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.3192"},{"key":"e_1_3_4_2_2","first-page":"1706","article-title":"Primary angle closure glaucoma in Chinese and Western populations","volume":"115","author":"Wang N","year":"2002","unstructured":"N Wang, H Wu, Z Fan, Primary angle closure glaucoma in Chinese and Western populations. 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