title: Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye.
abstract: Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.
authors.affiliation: USC Institute for Genetic Medicine and Graduate Program in Medical Biology, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Aditi
authors.initials: A
authors.lastname: Bauskar
authors.affiliation: Southern California Clinical & Translational Science Institute and Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.affiliation: The Schepens Eye Research Institute, Massachusetts Eye & Ear and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jerome
authors.initials: J
authors.lastname: Mauris
authors.affiliation: The Schepens Eye Research Institute, Massachusetts Eye & Ear and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Pablo
authors.initials: P
authors.lastname: Argüeso
authors.affiliation: USC Eye Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Heur
authors.affiliation: Research Microscopy and Histology Core, Department of Pathology, Saint Louis University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Nagel
authors.affiliation: Department of Pathology and Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Kolar
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
authors.affiliation: Center for Craniofacial Molecular Biology, Division of Biomedical Sciences, University of Southern California, Herman Ostrow School of Dentistry of USC, Los Angeles, California, United States of America.
authors.forename: Janet
authors.initials: J
authors.lastname: Moradian-Oldak
authors.affiliation: New England Eye Center/Department of Ophthalmology and Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Noorjahan
authors.initials: N
authors.lastname: Panjwani
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
authors.affiliation: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: USC Institute for Genetic Medicine and Departments of Cell & Neurobiology and Ophthalmology, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States of America.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Fini
authors.affiliation: USC Institute for Genetic Medicine and Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shinwu
authors.initials: S
authors.lastname: Jeong
mesh_terms: D000287:Administration, Topical; D000818:Animals; D051152:Clusterin / Q000494:pharmacology / Q000627:therapeutic use*; D019610:Cytoprotection / Q000187:drug effects; D003890:Desiccation; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000473:pathology; D005123:Eye / Q000187:drug effects / Q000473:pathology*; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013666:Tears / Q000378:metabolism
chemical_list: D051152:Clusterin; D037502:Galectin 3; C485095:Lgals3 protein, mouse