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Zhao et al. Journal of Neuroinflammation (2017) 14:14 DOI 10.1186/s12974-016-0775-RESEARCHOpen AccessPhotoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degenerationLei Zhao1, Jun Li1,2,3, Yingmei Fu1,4, Mengxue Zhang1, Bowen Wang1, Jonathan Ouellette5, Pawan K. Shahi6,9, Bikash R. Pattnaik6,8,9, Jyoti J. Watters5, Wai T. Wong7 and Lian-Wang Guo1,8*AbstractBackground: The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) “read” (bind) histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation. These epigenetic “readers” play crucial roles in pathogenic processes such as inflammation. The role of BETs in influencing the degenerative process in the retina is however unknown. Methods: We employed the rd10 mouse model (Pde6brd10 mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration. Results: Inhibition of BET activity by intravitreal delivery of JQ1, a BET-specific inhibitor binding both Brom1 and Brom2, ameliorated photoreceptor degeneration and improved electroretinographic function. Rescue effects of JQ1 were related to the suppression of retinal microglial activation in vivo, as determined by decreased immunostaining of activation markers (IBA1, CD68, TSPO) and messenger RNA (mRNA) levels of inflammatory cytokines in microglia purified from rd10 retinas. JQ1 pre-treatment also suppressed microglial activation in vitro, decreasing microglial proliferation, migration, and mRNA expression of inflammatory cytokines (TNF, MCP-1, IL-1, IL-6, and RANTES). Expression of BET2, but not BET3 and BET4, was significantly elevated during photoreceptor degeneration at postnatal day (PN)24 in retinas of rd10 mice relative to age-matched wild-type controls. siRNA knockdown of BET2 but not BET4, and the inhibitor of Brom2 (RVX208) but not of Brom1 (Olinone), decreased microglial activation. Conclusions: These findings indicate that BET inhibition rescues photoreceptor degeneration likely via the suppression of microglial activation and AZD3759 web implicates BET interference as a potential therapeutic strategy for the treatment of degenerative retinal diseases. Keywords: Bromodomain and extraterminal domain (BET) proteins, Epigenetic readers, Retinal degeneration, Microglial activation, JQ1, rd10 miceBackground Retinitis pigmentosa (RP) is a major blinding disease characterized by photoreceptor degeneration arising predominantly from mutations in genes expressed in photoreceptor or RPE cells [1, 2]. Despite extensive studies and trials of various means, e.g., antioxidants and* Correspondence: [email protected] 1 Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA 8 McPherson Eye Research Institute, University of Wisconsin, Madison, WI 53705, USA Full list of author information is available at the end of the articlestem cell therapy, to preserve or replace photorec.
