miR-146a-5p mitigates ethanol-induced neuroinflammation by targeting Btg2-dependent microglial activation

Chronic alcohol exposure leads to progressive neurodegeneration, primarily driven by sustained neuroinflammation and microglial activation. While microRNAs are key regulators of neuroimmune responses, the specific role of miR-146a-5p and its downstream targets in ethyl alcohol (EtOH)-induced neuroinflammatory injury remain poorly understood.

A chronic EtOH exposure model was established in C57BL/6 mice and BV-2 microglial cells. Neuroinflammatory damage was assessed using behavioral tests (Morris water maze), apoptosis assays, cytokine quantification, and immunostaining. The regulatory relationship between miR-146a-5p and its target gene Btg2 was investigated using luciferase reporter and RNA pull-down assays, combined with gain-of-function approaches.

EtOH exposure significantly downregulated miR-146a-5p expression in both mouse hippocampal tissue and BV-2 cells. Overexpression of miR-146a-5p in vivo improved spatial learning and memory, reduced neuronal apoptosis, and attenuated microglial activation and pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) production. Mechanistically, Btg2 was identified as a direct target of miR-146a-5p. EtOH-induced Btg2 upregulation was reversed by miR-146a-5p overexpression in vitro. Importantly, restoring Btg2 expression abolished the anti-inflammatory and anti-apoptotic effects of miR-146a-5p in EtOH-treated BV-2 cells.

This study identifies the miR-146a-5p/Btg2 axis as a critical regulator of EtOH-induced microglial activation and neuroinflammation. Targeting this pathway may offer a promising therapeutic strategy for alcohol-related neurodegeneration.