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

Wang, Changshui, Feng, Lei, Zhu, Li, Wu, Linlin, Chen, Beibei, Cui, Changmeng, Yang, Mengqi, Gao, Yahao, Jiang, Pei·2023·Cell Death & Disease
DOI 10.1038/s41419-023-06173-5PMC PMC10541416
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Abstract

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.

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Metadata

Authors
Wang, C., Feng, L., Zhu, L., Wu, L., Chen, B., Cui, C., Yang, M., Gao, Y., & Jiang, P.
ORCID
Jiang, Pei
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2023-09-29
Volume
14
Issue
9
ISSN
2041-4889
DOI
10.1038/s41419-023-06173-5
PMC
PMC10541416
Cited by
16
References
5
Language
en
Licence
Funders
  • National Natural Science Foundation of China (82272253, 81602846, 82302795, 81901954)
  • Taishan Scholar Project of Shandong Province (tsqn201812159)
  • Natural Science Foundation of Shandong Province (ZR2021MH145, ZR2023QH094)
  • Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation of Jining Medical University

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