Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells

• Published in: The Journal of immunology (1950) Vol. 198; no. 3; pp. 1093 - 1103
• Main Authors: Eskandarpour, Malihe, Alexander, Robert, Adamson, Peter, Calder, Virginia L
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.02.2017
• Subjects: Adoptive transfer; Animals; Autoimmune diseases; Autoimmune Diseases - drug therapy; CD4 antigen; Chromosomal Proteins, Non-Histone - antagonists & inhibitors; Cytokines - biosynthesis; Down-Regulation; Experimental autoimmune uveitis; Experimental autoimmune uveoretinitis; Female; Forkhead Transcription Factors - analysis; Foxp3 protein; Helper cells; Inhibitors; Interleukin 10; Interleukin 22; Lymphocytes; Lymphocytes T; Mice; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - physiology; Nuclear Receptor Subfamily 1, Group F, Member 3 - analysis; Pathogenicity; Pathogens; Proteins; Receptors, CCR6 - analysis; Retina; Retina - drug effects; Retina - immunology; Retinoic acid; Th1 Cells - immunology; Th17 Cells - drug effects; Th17 Cells - immunology; Transcription Factors - antagonists & inhibitors; Transcription Factors - physiology; Tumor Necrosis Factor-alpha - analysis; Uveitis; Uveitis - drug therapy
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600735

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.