Cerebral endothelial cell-derived extracellular vesicles regulate microglial polarization and promote autophagy via delivery of miR-672-5p

• Published in: Cell death & disease Vol. 14; no. 9; p. 643
• Main Authors: Wang, Changshui, Feng, Lei, Zhu, Li, Wu, Linlin, Chen, Beibei, Cui, Changmeng, Yang, Mengqi, Gao, Yahao, Jiang, Pei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.09.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/51; 13/89; 38/39; 42/41; 631/80/39; 64/60; 96/21; Animals; Antibodies; Autophagy; Autophagy - genetics; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell interactions; Endothelial Cells; Extracellular vesicles; Extracellular Vesicles - genetics; Homeostasis; Immune response; Immunology; Inflammasomes; Inflammation; Kinases; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Mice; Microglia - metabolism; Microglial cells; MicroRNAs - genetics; miRNA; Molecular modelling; Neuroprotection; NF-κB protein; Phenotypes; Polarization; TAK1 protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06173-5

The interaction between cerebral endothelial cells (CEC) and brain parenchymal cells is critical to maintain neurovascular homeostasis, whereas extracellular vesicles (EVs) are essential to mediate the cell–cell communication. Previous researches demonstrated that CEC-derived EVs (CEC-EVs) confer neuroprotective actions. However, the molecular mechanisms remain unknown. In this study, we isolated EVs from CEC and assessed their immune-regulatory actions in microglial cells and mice following lipopolysaccharide (LPS) exposure. We found that CEC-EVs treatment significantly ameliorated LPS-induced inflammatory activation, shifting microglial polarization from pro-inflammatory phenotype to anti-inflammatory phenotype. Meanwhile, microglial cells can effectively internalize CEC-EVs and this process was further enhanced by immune activation. Next, the miRNA microarray analysis revealed that CEC-EVs increased expression of miR-672-5p, which was demonstrated to be the cargo of CEC-EVs. TGFβ-activated kinase 1 (TAK1)-binding proteins 2 (TAB2) was identified to be the target of miR-672-5p. Through inhibiting TAB2, miR-672-5p derived from CEC-EVs suppressed TAK1-TAB signaling and thereby mitigating the downstream NF-κB activation. Furthermore, we found that by delivering miR-672-5p, CEC-EVs promoted autophagy and hence stimulating autophagic degradation of NLRP3 inflammasome. Our work firstly revealed the neuroimmune-modulating actions of CEC-EVs and further demonstrated that miR-672-5p secreted from CEC-EVs inhibits microglial pro-inflammatory polarization and facilitates autophagic process via targeting TAB2.