AUTHOR=Periyasamy Palsamy , Singh Seema , Oladapo Abiola , Kannan Muthukumar , Buch Shilpa 

TITLE=Role of lncRNA Xist-miR-124-CCL2 axis in HIV Tat-mediated microglial activation and neuroinflammation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1558842

DOI=10.3389/fimmu.2025.1558842

ISSN=1664-3224

ABSTRACT=IntroductionHIV proteins, such as the Transactivator of transcription (Tat), mediate neuroinflammation in the central nervous system by promoting the release of pro-inflammatory cytokines and chemokines. Long noncoding RNAs (lncRNAs) regulate gene expression by sponging microRNAs (miRs), but their role in HIV Tat-mediated microglial activation remains poorly understood. This study aimed to investigate the involvement of the lncRNA Xist–miR-124–CCL2 axis in HIV Tat-exposed microglial cells.MethodsMouse primary microglial cells were exposed to HIV Tat, and the expression of lncRNA Xist, miR-124, and CCL2 was evaluated using qPCR, Western blotting, and ELISA. Dual-luciferase reporter and Argonaute immunoprecipitation assays were used to confirm molecular interactions. Functional experiments involved lncRNA Xist silencing and miR-124 overexpression. In vivo validation was performed using doxycycline-inducible HIV Tat transgenic mice.ResultsHIV Tat significantly upregulated lncRNA Xist and downregulated miR-124 expression in mouse primary microglial cells. miR-124 was identified as a direct target of lncRNA Xist and the 3′-UTR of CCL2. Silencing lncRNA Xist or overexpressing miR-124 reduced HIV Tat-induced CCL2 expression and microglial activation. In vivo studies corroborated these findings, with doxycycline-fed iTat mice showing elevated lncRNA Xist and CCL2 levels and reduced miR-124 expression in the frontal cortex.DiscussionOur findings identify a novel regulatory axis whereby HIV Tat-induced upregulation of lncRNA Xist sponges miR-124, leading to CCL2 overexpression and microglial activation. Targeting the lncRNA Xist–miR-124–CCL2 pathway may represent a promising therapeutic strategy to mitigate neuroinflammation associated with NeuroHIV.