Curcumin Regulates Microglia Polarization to Alleviate Ischemic Stroke by Targeting microRNA-205-5p/Kruppel-Like Factor 2 (KLF2)/Activating Transcription Factor 2 (ATF2) Axis.

Abstract

Ischemic stroke (IS) often causes fearful sequela, even death. Curcumin was beneficial to IS, but its underlying molecular mechanism is unclear. Mice were subjected to middle cerebral artery occlusion (MCAO) surgery, and BV-2 cells were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) induction to establish IS models in vivo and in vitro. Abundance of genes and proteins was determined using quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and western blot. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Modified neurological severity score (mNSS), corner test, foot fault test, adhesive removal test, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were applied to evaluate the brain injury of mice. The correlation between miR-205-5p and Kruppel-like factor 2 (KLF2) was affirmed using dual luciferase reporter assay. Our results revealed that curcumin alleviated brain damage in MCAO mice through driving microglia M2 polarization. Of note, curcumin resulted in decreased miR-205-5p expression in MCAO mice. miR-205-5p knockdown resulted in promoted microglia M2 polarization in OGD/R conditions and achieved similar results to curcumin treatment in MCAO mice. Moreover, curcumin played a promoting role in microglia M2 polarization under OGD/R conditions, while miR-205-5p overexpression or KLF2 knockdown abolished these effects. On the mechanism, miR-205-5p was a target of curcumin, and miR-205-5p further interacted with KLF2 to inhibit activating transcription factor 2 (ATF2) expression. miR-205-5p, decreased by curcumin, suppressed microglia M2 polarization to worsen IS injury through the mediating KLF2/ATF2 axis.