Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation

• Published in: Neuropharmacology 2017-10, Vol.125, p.376-385
• Main Authors: Avila, Diana V., Myers, Scott A., Zhang, JingWen, Kharebava, Giorgi, McClain, Craig J., Kim, Hee-Yong, Whittemore, Scott R., Gobejishvili, Leila, Barve, Shirish
• Format: Article
• Language: English
• Subjects: Alcohol; cAMP; Microglial activation; Neuroinflammation; Pde4b
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.08.011

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. •Chronic alcohol consumption induces peripheral endotoxemia leading to systemic and neuro-inflammation.•Chronic alcohol increases brain Pde4b expression and decreases cAMP levels.•Pharmacologic inhibition of Pde4b and Pde4b gene knockout, markedly attenuate alcohol-induced glial cell activation and brain inflammatory cytokine expression.•First report on the critical role of cAMP-specific Pde4b in alcohol-induced neuro-inflammation.•Targeting Pde4b expression/activity is a potential therapeutic strategy to mitigate alcohol-induced neuro-inflammation.