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

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.

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

“…Acute liver injury was significantly alleviated, and the survival rate of the mice increased. Studies have shown that SS can prevent the occurrence of D-GalN/ LPS-induced acute liver injury by regulating antiinflammatory and anti-apoptosis mechanisms [33,34], but the specific mechanism is unclear. Therefore, we further explored the protective mechanisms of SS extract on LPS and D-GalN-induced acute liver injury.…”

HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy

“…Pregnant C57BL/6N mice were purchased from Charles River Laboratories (Wilmington, MA USA). Primary cultures of mouse mixed glia were prepared from the cerebral cortices of 1-to 3-d-old C57BL/6 newborn pups as described previously [88,89]. Briefly, cerebral cortices from neonatal mice were dissected and freed of meninges.…”

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

“…Primary microglia were obtained as previously reported [57,58]. Briefly, brains were removed from newborn mice (1-3 days old) and carefully cut into 0.5-1-mm 3 pieces.…”