Pathogenic Role of Phosphodiesterase 4B (PDE4B) in Alcohol‐induced Neuro‐inflammation

Abstract

Chronic ethanol consumption significantly increases brain TLR4 expression and downstream inflammatory gene expression, contributing to microglial activation and neuro-inflammation. Our group has shown that TLR4 inducible PDE4 expression plays a major role in regulating inflammatory cytokine expression in alcohol exposed peripheral macrophages. Hence, we examined its role in alcohol-inducible activation of astroglial cells and neuro-inflammation. We utilized, C57Bl/6 wild-type (WT) and Pde4b-/-mice that were pair-fed or alcohol-fed for 4 weeks, Inhibition of PDE4 was achieved by treatment with a specific inhibitor rolipram (5mg/kg). Further, primary microglial cells were treated in vitro with ethanol (50mM) and LPS (100ng/ml). Results demonstrated that alcohol exposure increases PDE4B expression in brain tissue as well as primary microglial cells. Along with PDE4B, alcohol was also observed to induce activation of astroglial cells as indicated by an increase in glial fibrillary acidic protein - GFAP+ astrocytes and ionized calcium-binding adapter molecule 1 - IBA-1+ microglial cells. Importantly, alcohol-induced activation of astroglial cells was markedly attenuated in (i) Pde4b-/- mice and by (ii) pharmacologic inhibition of PDE4. These data show that PDE4B plays a critical role in regulating alcohol-induced neuro-inflammation and could serve as a significant therapeutic target.