title: Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells.
abstract: Experimental autoimmune uveitis (EAU), in which CD4+Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid-related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis.
authors.affiliation: University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom.
authors.forename: Malihe
authors.initials: M
authors.lastname: Eskandarpour
authors.affiliation: University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom.
authors.forename: Robert
authors.identifier: 0000-0003-4242-8550
authors.initials: R
authors.lastname: Alexander
authors.affiliation: University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom.
authors.forename: Peter
authors.identifier: 0000-0001-8234-1818
authors.initials: P
authors.lastname: Adamson
authors.affiliation: University College London Institute of Ophthalmology, London EC1V 9EL, United Kingdom v.calder@ucl.ac.uk.
authors.forename: Virginia L
authors.identifier: 0000-0003-1422-2926
authors.initials: VL
authors.lastname: Calder
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000032:analysis; D054399:Receptors, CCR6 / Q000032:analysis; D012160:Retina / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014605:Uveitis / Q000188:drug therapy*; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C498126:CCR6 protein, mouse; C498833:Foxp3 protein, mouse