Fig. 7

Proposed model for Ago2 regulation of the endothelial and glial crosstalk. LPS activation of the p38 signaling pathway promotes VE-cadherin downregulation and the transcription of mRNA related to pro-inflammatory mediators (e.g., cytokines). The translation of these transcripts is facilitated by low Ago2 levels and low RISC activity. These events trigger the activation of microglia and astrocytes associated with blood vessels, and cause neuronal damage. The exogenous application and internalization of Ago2, via NRP1, recuperates RISC activity, which is conducive to eNOS degradation and low NO, reducing glial activation and protecting neuronal cells. Ago2 argonaute-2, IL-6 interleukin-6, LPS lipopolysaccharide, mRNA messenger ribonucleic acid, NO nitric oxide, NRP1 neuropilin-1, p38 p38 mitogen-activated protein kinases signaling pathway, RISC RNA-induced silencing complex, TNF-α tumor necrosis factor alpha, TLR4 toll-like receptor 4, VE-cadherin vascular endothelial-cadherin