IL-4-polarized BV2 microglia cells promote angiogenesis by secreting exosomes

Abstract

Background. The microglia cell transfer has been shown to play a protective role in ischemic stroke. Microglia cells may play this nerve-protective role via the promotion of angiogenesis. However, the underlying mechanisms are largely unknown and need further investigation. Objectives. The aim of this study was to investigate the pro-angiogenesis effects of unpolarized, interleukin 4 (IL-4)-polarized or lipopolysaccharide (LPS)-polarized BV2 microglia cells both in vivo and in vitro. We also investigated the potential mechanisms of these pro-angiogenesis effects. Material and methods. BV2 cells were polarized using phosphate-buffered saline (PBS), LPS or IL-4, respectively. The gene expression pattern was analyzed with reverse transcription polymerase chain reaction (RT-PCR). The transfer of polarized BV2 cells was performed with an intravenous injection into mice 45 min after the middle cerebral artery (MCA) occlusion. Angiogenin expression was assessed with immunofluorescence. We also examined the angiogenesis effect of polarized BV2 cells and their exosomes through 3-dimensional co-cultures in vitro. Finally, the microRNA (miRNA) profiles of exosomes released by BV2 cells under different polarization conditions were examined using miRNA microarray. Results. The IL-4-polarized BV2 transplantation promoted angiogenin expression in the ischemic brain. Interleukin 4-polarized microglia increased the tube formation of endothelial cells by secreting exosomes. The miRNA profiles of exosomes released by BV2 cells under different polarization conditions were different. Exosomes from IL-4-polarized BV2 cells contained higher amounts of miRNA-26a compared to those from the LPS-polarized and unpolarized BV2 cells. Conclusions. Interleukin 4-polarized microglia cells might ameliorate the damage caused by ischemic stroke by promoting angiogenesis through the secretion of exosomes containing miRNA-26a.

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke

“…In the present study, TWS119 facilitated post-stroke angiogenesis in the ischemic brain, but failed to directly promote angiogenesis in OGD endothelial cells. Evidence revealed that microglia in anti-inflammatory phenotype promote angiogenesis [39]. Using a conditioned medium transfer system, we found that TWS119 promoted angiogenesis of OGD endothelial cells via anti-inflammatory phenotype microglia-mediated amelioration of inflammatory microenvironment, suggesting a proangiogenic effect of TWS119 in anti-inflammatory phenotype polarization-dependent manner.…”

Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery

“…There is evidence of crosstalk between microglia and endothelial cells. Polarization of microglia induced by IL-4 increased miR-26a in microglia-generated exosomes, which may promote tube formation in vitro and angiogenesis in vivo after ischemia [62]. Thus, exosomes exerted direct and indirect effects for repairing and regenerating brains after stroke.…”

Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia

“…On the other hand M2 microglia-derived exosomes containing miR-124 were shown to be absorbed by neurons and further boost neuronal survival by targeting the ubiquitinspecific protease 14 (Song et al, 2019). In addition, IL-4stimulated microglia was suggested to promote angiogenesis by secreting exosomes containing miR-26a, thereby reducing the damage caused by ischemic stroke (Tian et al, 2019). These studies indicate that M2 microglia play a protective role against ischemic stroke through miRNA-mediated regulation.…”