title: Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye.
abstract: The concept of innate immunity has been expanded to recognize environmental pathogens other than microbial components. However, whether and how the innate immunity is initiated by epithelium in response to environmental physical challenges such as low humidity and high osmolarity in an autoimmune disease, dry eye, is still largely unknown. Using two experimental dry eye models, primary human corneal epithelial cultures exposed to hyperosmolarity and mouse ocular surface facing desiccating stress, we uncovered novel innate immunity pathway by ocular surface epithelium, where oxidized mitochondrial DNA induces imbalanced activation of NLRP3/NLRP6 inflammasomes via stimulation of caspase-8 and BRCC36 in response to environmental stress. Activated NLRP3 with suppressed NLRP6 stimulates caspase-1 activation that leads to IL-1β and IL-18 maturation and secretion. NLRP3-independent caspase-8 noncanonically activates caspase-1 via reciprocal regulation of NLRP3/NLRP6-mediated inflammasomes. Reactive oxygen species-induced mitochondrial DNA oxidative damage and BRCC36 deubiquitinating activity provide a missing link and mechanism by which innate immunity responds to environmental stress via caspase-8-involved NLRP3/NLRP6 inflammasomes.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: chiwei@mail.sysu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Chi
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA; Second Hospital of Tianjin Medical University, Tianjin, China. Electronic address: 849795145@qq.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Hua
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA; School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China. Electronic address: Xin.Chen@bcm.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: Fang.Bian@bcm.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: yuanxy_cn@hotmail.com.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: Xiaoran.Wang@bcm.edu.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Wang
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA; School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China. Electronic address: Ding.Chen@bcm.edu.
authors.forename: Ding
authors.initials: D
authors.lastname: Chen
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA; School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China. Electronic address: 2335281147@qq.com.
authors.forename: Ruzhi
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: zhijiel@bcm.edu.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Electronic address: yzliu62@yahoo.com.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: cintiadp@bcm.edu.
authors.forename: Cintia S
authors.initials: CS
authors.lastname: de Paiva
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: stevenp@bcm.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA. Electronic address: dequanl@bcm.edu.
authors.forename: De-Quan
authors.initials: DQ
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015551:Autoimmunity; D053181:Caspase 8 / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D015352:Dry Eye Syndromes / Q000276:immunology*; D004781:Environmental Exposure / Q000009:adverse effects; D019573:Epithelium, Corneal / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C468563:NLRP6 protein, human; D017382:Reactive Oxygen Species; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes; D053181:Caspase 8
keywords: Caspase activity; Environmental stress; Inflammasome activation; Innate immunity; Mitochondrial DNA; NLR proteins