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Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells
You, Tingting; Cheng, Yufang; Zhong, Jiahong; Bi, Bingtian; Zeng, Bingqing; Zheng, Wenhua; Wang, Haitao; Xu, Jiangping
2017-11
Source PublicationACS CHEMICAL NEUROSCIENCE
ISSN1948-7193
Volume8Issue:11Pages:2381-2392
AbstractInhibition of phosphodiesterase 4 (PDE4) suppressed the inflammatory responses in the brain. However, the underlying mechanisms are poorly understood. Roflupram (ROF) is a novel PDE4 inhibitor. In the present study, we found that ROF enhanced the level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62 in microglial BV-2 cells. Enhanced fluorescent signals were observed in BV-2 cells treated with ROF by Lysotracker red and acridine orange staining. In addition, immunofluorescence indicated a significant increase in punctate LC3. Moreover, beta amyloid 25-35 (A beta(25-35)) or lipopolysaccharide (LPS) with ATP was used to activate inflammasome. We found that both LPS plus ATP and A beta(25-35) enhanced the conversion of pro-caspase-1 to cleaved-caspase-1 and increased the production of mature IL-1 beta in BV-2 cells. Interestingly, these effects were blocked by the treatment of ROF. Consistently, knocking down the expression of PDE4B in primary microglial cells led to enhanced level of LC-3 II and decreased activation of inflammasome. What's more, Hoechst staining showed that ROF decreased the apoptosis of neuronal N2a cells in conditioned media from microglia. Our data also showed that ROF dose-dependently enhanced autophagy, reduced the activation of inflammasome and suppressed the production of IL-1 beta in mice injected with LPS. These effects were reversed by inhibition of microglial autophagy. These results put together demonstrate that ROF inhibits inflammasome activities and reduces the release of IL-1 beta by inducing autophagy. Therefore, ROF could be used as a potential therapeutic compound for the intervention of inflammation-associated diseases in the brain.
KeywordPhosphodiesterase 4 roflupram autophagy inflammasome microglia neuroinflammation
DOI10.1021/acschemneuro.7b00065
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal ; Neurosciences
WOS IDWOS:000415786400008
PublisherAMER CHEMICAL SOC
The Source to ArticleWOS
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被引频次[WOS]:10   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题University of Macau
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You, Tingting,Cheng, Yufang,Zhong, Jiahong,et al. Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells[J]. ACS CHEMICAL NEUROSCIENCE,2017,8(11):2381-2392.
APA You, Tingting.,Cheng, Yufang.,Zhong, Jiahong.,Bi, Bingtian.,Zeng, Bingqing.,...&Xu, Jiangping.(2017).Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells.ACS CHEMICAL NEUROSCIENCE,8(11),2381-2392.
MLA You, Tingting,et al."Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells".ACS CHEMICAL NEUROSCIENCE 8.11(2017):2381-2392.
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