HMGB1/IL-1β complexes regulate neuroimmune responses in alcoholism

Neuroimmune activation is a key feature of the pathologies of numerous psychiatric disorders including alcoholism, depression, and anxiety. Both HMGB1 and IL-1 beta have been implicated in brain disorders. Previous studies find HMGB1 and IL-1 beta form heterocomplexes in vitro with enhanced immune responses, lead to our hypothesis that HMGB1 and IL-1 beta heterocomplexes formed in vivo to contribute to the pathology of alcoholism. HMGB1/IL-1 beta heterocomplexes were prepared in vitro and found to potentiate IL-1 beta receptor proinfiammatory gene induction compared to IL-1 beta alone in hippocampal brain slice culture. These HMGB1/IL-1 beta complexes were found to be increased in post-mortem human alcoholic hippocampus by co-immunoprecipiation. In mice, acute binge ethanol induced both HMGB1 and IL-1 beta in the brain and plasma. HMGB1 and IL-1 beta complexes were found only in mouse brain, with confocal microscopy revealing an ethanol-induced HMGB1 and IL-1 beta cytoplasmic co-localization. Surprisingly, IL-1 beta was found primarily in neurons. Studies in hippocampal brain slice culture found ethanol increased HMGB1/IL-1 beta complexes in the media. These studies suggest a novel neuroimmune mechanism in the pathology of alcoholism. Immunogenic HMGB1/IL-1 beta complexes represent a novel target for immune modulatory therapy in alcohol use disorders, and should be investigated in other psychiatric diseases that involve a neuroimmune component. (C) 2017 Elsevier Inc. All rights reserved.