title: Impaired autophagy in macrophages promotes inflammatory eye disease.
abstract: Autophagy is critical for maintaining cellular homeostasis. Organs such as the eye and brain are immunologically privileged. Here, we demonstrate that autophagy is essential for maintaining ocular immune privilege. Deletion of multiple autophagy genes in macrophages leads to an inflammation-mediated eye disease called uveitis that can cause blindness. Loss of autophagy activates inflammasome-mediated IL1B secretion that increases disease severity. Inhibition of caspase activity by gene deletion or pharmacological means completely reverses the disease phenotype. Of interest, experimental uveitis was also increased in a model of Crohn disease, a systemic autoimmune disease in which patients often develop uveitis, offering a potential mechanistic link between macrophage autophagy and systemic disease. These findings directly implicate the homeostatic process of autophagy in blinding eye disease and identify novel pathways for therapeutic intervention in uveitis.
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Santeford
authors.affiliation: b Steven W. Dezii Translational Vision Research Facility, Stephen A. Wynn Institute for Vision Research Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa , Iowa City , IA , USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Wiley
authors.affiliation: c Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Sonya
authors.initials: S
authors.lastname: Bamba
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Rei
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Gdoura
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferguson
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: P Kumar
authors.initials: PK
authors.lastname: Rao
authors.affiliation: d Department of Cancer Biology , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.affiliation: e Department of Inflammation Biology , Tokushima University , Tokushima , Japan.|f Institute for Enzyme Research, Tokushima University , Tokushima , Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.affiliation: g Laboratory of Host Defense, WPI Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University , Osaka , Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: h Broad Institute of Massachusetts Institute of Technology and Harvard University , Cambridge , MA , USA.|i Center for Computational and Integrative Biology and Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.affiliation: c Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.|j Department of Molecular Microbiology , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Washington University School of Medicine , St. Louis , MO , USA.|k Department of Developmental Biology , Washington University School of Medicine , St. Louis , MO , USA.|l Neuroscience Program, Washington University School of Medicine , St. Louis , MO , USA.|m Department of Medicine , Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Apte
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071183:Autophagy-Related Proteins / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005128:Eye Diseases / Q000473:pathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000473:pathology* / Q000648:ultrastructure; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014605:Uveitis / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C518959:ATG16L1 protein, human; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta
keywords: autophagy; eye; inflammasome; innate immunity; macrophage; uveitis