MiR-223-3p inhibits hippocampal neurons injury and exerts anti- anxiety/depression-like behaviors by directly targeting NLRP3.

Abstract

Anxiety/depression disorders are among the most common neuropsychiatric conditions, and inflammation plays a significant role in their regulation. The involvement of miRNAs in the initiation, progression, and outcomes of anxiety disorders has been widely reported. Here, a decline in miR-223-3p expression was noticed in both IL-8-induced HT-22 cells and a rat model of anxiety/depression disorders treated with chronic unpredictable mild stress (CUMS). Our findings indicate that the overexpression of miR-223-3p significantly alleviates the effects of IL-8 on cell viability, inflammation, and oxidative stress in HT-22 cells, as verified by CCK-8 assay, ELISA assay, and flow cytometry. Through bioinformatics and luciferase reporter assays, NLRP3 was identified as a direct target of miR-223-3p. The inhibition of NLRP3 significantly reduced IL-8-induced damage to hippocampal neurons, while overexpression of NLRP3 reversed the protective effects of miR-223-3p. Moreover, increasing miR-223-3p levels significantly attenuated CUMS-induced anxiety/depression -like behaviors, such as decreased time in center in the open field test (OFT) and decreased time in open arm in the plus-maze test (EPM). The overexpression of miR-223-3p resulted in significant reductions in TNF-α, IL-1β, and SOD levels, an increase in MDA activity, as well as upregulation of cyclic adenosine monophosphate (cAMP), phosphorylated cAMP response element-binding protein (p-CREB), and brain-derived neurotrophic factor (BDNF) in the hippocampus. Overexpression of NLRP3 also reversed the effects of miR-223-3p in vivo. Thus, our research suggests that miR-223-3p can improve anxiety/depression-like behavior and inhibit hippocampal neuronal injury by targeting NLRP3, demonstrating its considerable anti-anxiety potential.