The role of exosomes on brain inflammation and microglia activation in alcohol use disorders

Excessive alcohol consumption, the defining characteristic of an alcohol use disorder (AUD), damages the nervous system, underlying the cognitive impairments observed in those individuals with an AUD. Both clinical and preclinical evidence from our lab and others suggests that microglia/macrophages play a key role in alcohol-induced neuroinflammation and neurotoxicity. Various types of microglia/macrophages have been identified on the basis of their function: classically activated (M1) proinflammatory microglia/macrophages and alternatively activated (M2) growth-promoting microglia/macrophages.However, the mechanisms responsible for microglia/macrophage phenotype regulation by alcohol are poorly understood. MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of microglia/macrophage differentiation and polarization. Although miRNAs act mainly in a cell-autonomous manner, accumulating evidence suggests that miRNAs can be packed into exosomes for intercellular signaling. Exosomes are small, 50-150 nm vesicles that secreted into the extracellular space and fuse to neighboring cells to release their contents (proteins, mRNAs and miRNAs), thus serving as a novel intercellular genetic regulatory mechanism. Many cells in the nervous systems have the capacity to release exosomes, including neurons. Our preliminary data demonstrated neuronal exosomes contain miRNAs that can alter microglia/macrophage gene expression and regulate their activation phenotypes. Therefore, we hypothesize that miRNA-containing exosomes derived from alcohol-treated neurons can convey messages to microglia/macrophage and modulate their activation and function, and thus contribute to neuroinflammation in AUDs. We will test this hypothesis with the following specific aims: Aim 1: We will identify the miRNA elements that regulate microglia/macrophage activation and function in ethanol-treated neuron exosomes. Aim 2. We will determine the role of brain exosome derived from 4-day Binge rat brain in mediating brain inflammation and microglia activation. This proposal is novel in exploring the role of exosomes on brain communication between neuron and macrophage/microglia in AUDs. This unique and novel regulatory mechanism in neuron-to-microglia communication will provide new insight into miRNA-mediated microglia activation in physiological and pathological conditions. The data generated from this investigation will lay the groundwork for a future competitive R01 proposal on the role of exosomes in AUDs.