title: Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma.
abstract: Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. 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-1β expression and RGC death via a caspase-1-dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent 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-1β production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Chi
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Yingting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Frances
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Hong
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and.
authors.forename: Jian
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.affiliation: Department of Ophthalmology and Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093 kang.zhang@gmail.com zhuoyh@mail.sysu.edu.cn.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; and kang.zhang@gmail.com zhuoyh@mail.sysu.edu.cn.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Zhuo
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D005136:Eye Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; C492716:Nlrp3 protein, mouse; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; D053181:Caspase 8; D020170:Caspase 1
keywords: cell apoptosis; retinal ischemia/reperfusion injury