Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation.
Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation.
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DOI：
10.1016/j.neuropharm.2017.08.011
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发表时间：
2017-10
影响因子：
4.7
通讯作者：
Barve S
中科院分区：
文献类型：
--
作者：
Avila DV;Myers SA;Zhang J;Kharebava G;McClain CJ;Kim HY;Whittemore SR;Gobejishvili L;Barve S
越来越明显的是，酒精诱导的、肠道介导的外周内毒素血症在胶质细胞活化和神经炎症中发挥着重要作用。使用慢性酒精喂养的小鼠模型，我们研究了内毒素和精氨酸反应性Pde 4亚家族B（Pde 4 B）表达在酒精诱导的神经炎症中的因果作用。药理学和遗传学方法都被用来确定Pde 4 b的调节作用。在C57 B1/6野生型（WT）酒精饲喂（WT-AF）动物中，酒精显著诱导外周内毒素血症和脑组织中的Pde 4 b表达，伴随cAMP水平的降低。此外，沿着Pde 4 b，存在星形胶质细胞和小胶质细胞的强烈活化，伴随炎性细胞因子（TNFα、IL-1β、Mcp-1和IL-17）和广义炎性标志物考克斯-2的显著增加。在细胞水平，酒精和炎症介质，特别是LPS，TNFα和Hmgb 1显著激活小胶质细胞（Iba-1表达），并选择性诱导Pde 4 b表达，Pde 4a和d亚型变化极小或无变化。相比之下，在用Pde 4特异性药理学抑制剂咯利普兰处理的WT小鼠和Pde 4 b −/−小鼠中，酒精诱导的脑cAMP水平降低被完全抑制。此外，所有观察到的酒精诱导的脑炎症的标志物显着减弱。重要的是，在Pde 4 b −/−小鼠中，全身性内毒素血症（LPS给药）诱导的胶质细胞活化也显著降低。总之，这些发现强烈支持Pde 4 b在协调酒精诱导的外周内毒素血症介导的神经炎症中起关键作用的观点，并且可以作为重要的治疗靶点。
It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels. Further, along with Pde4b, there was a robust activation of astrocytes and microglia accompanied by significant increases in the inflammatory cytokines (Tnfα, Il-1β, Mcp-1 and Il-17) and the generalized inflammatory marker Cox-2. At the cellular level, alcohol and inflammatory mediators, particularly LPS, Tnfα and Hmgb1 significantly activated microglial cells (Iba-1 expression) and selectively induced Pde4b expression with a minimal to no change in Pde4a and d isoforms. In comparison, the alcohol-induced decrease in brain cAMP levels was completely inhibited in WT mice treated with the Pde4 specific pharmacologic inhibitor rolipram and in Pde4b−/− mice. Moreover, all the observed markers of alcohol-induced brain inflammation were markedly attenuated. Importantly, glial cell activation induced by systemic endotoxemia (LPS administration) was also markedly decreased in Pde4b−/− mice. Taken together, these findings strongly support the notion that Pde4b plays a critical role in coordinating alcohol-induced, peripheral endotoxemia mediated neuro-inflammation and could serve as a significant therapeutic target.
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DOI：
10.1016/j.alcohol.2008.12.009
发表时间：
2009-03
期刊：
Alcohol (Fayetteville, N.Y.)
影响因子：
--
作者：
Forsyth CB;Farhadi A;Jakate SM;Tang Y;Shaikh M;Keshavarzian A
通讯作者：
Keshavarzian A
影响因子：
6.2
作者：
Ghosh, Mousumi;Garcia-Castillo, Daniela;Aguirre, Vladimir;Golshani, Roozbeh;Atkins, Coleen M.;Bramlett, Helen M.;Dietrich, W. Dalton;Pearse, Damien D.
通讯作者：
Pearse, Damien D.
DOI：
10.1002/path.4760
发表时间：
2016-09
期刊：
The Journal of pathology
影响因子：
--
作者：
Avila DV;Barker DF;Zhang J;McClain CJ;Barve S;Gobejishvili L
通讯作者：
Gobejishvili L
影响因子：
10.6
作者：
Crews, Fulton T.;Qin, Liya;Sheedy, Donna;Vetreno, Ryan P.;Zou, Jian
通讯作者：
Zou, Jian
影响因子：
5.3
作者：
Alfonso-Loeches, Silvia;Pascual-Lucas, Maya;Guerri, Consuelo
通讯作者：
Guerri, Consuelo