Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling

Palsamy Periyasamy, Ke Liao, Yeon Hee Kook, Fang Niu, Shannon E. Callen, Minglei Guo, Shilpa J Buch

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Cocaine is known to activate microglia both in vitro and in vivo. High expression of microglial Toll-like receptors (TLRs) and their downstream signal transducers play critical roles in determining microglial activation status. Emerging reports have also demonstrated that cocaine can enhance the strength of TLR signaling. Detailed molecular mechanisms underlying this phenomenon, however, remain elusive. In this study, we investigated the role(s) of miR-124 in regulating microglial TLR4 signaling in the context of cocaine. Herein, we found a dose- and time-dependent upregulation of KLF4 in cocaine-exposed BV-2 cells and rat primary microglial cells (rPMs). KLF4 also identified as a novel 3′-UTR target directly regulated by miR-124. In parallel, miR-124 regulated multiple TLR4 signaling molecules including TLR4, MyD88, TRAF6, and IRAK1. Repeated doses of cocaine (20 mg/kg; i.p.) administration in mice for 7 days further validated the in vitro key findings. Also, miR-124 overexpression significantly blocked the cocaine-mediated upregulation of pro-inflammatory cytokines. In contrast, miR-124 overexpression notably increased the expression of anti-inflammatory mediators in cocaine-exposed microglial cells. Intriguingly, stereotactic administration of lentivirus-miR-124 in the striatum significantly inhibited cocaine-mediated microglial activation and locomotor hyperactivity in vivo. In summary, these findings implicate the role of miR-124 in regulating TLR4 signaling, thereby indicating a new pathway responsible for cocaine-mediated microglial activation.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - May 6 2017

Fingerprint

Microglia
Cocaine
Down-Regulation
Toll-Like Receptors
Up-Regulation
TNF Receptor-Associated Factor 6
Lentivirus
3' Untranslated Regions
Transducers
Anti-Inflammatory Agents
Cytokines

Keywords

  • Cocaine
  • Microglial cells
  • miR-124
  • MyD88
  • Neuroinflammation
  • TLR4
  • TRAF6

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling. / Periyasamy, Palsamy; Liao, Ke; Kook, Yeon Hee; Niu, Fang; Callen, Shannon E.; Guo, Minglei; Buch, Shilpa J.

In: Molecular Neurobiology, 06.05.2017, p. 1-15.

Research output: Contribution to journalArticle

Periyasamy, Palsamy ; Liao, Ke ; Kook, Yeon Hee ; Niu, Fang ; Callen, Shannon E. ; Guo, Minglei ; Buch, Shilpa J. / Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling. In: Molecular Neurobiology. 2017 ; pp. 1-15.
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