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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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Figures

Fig. 1 LPS treatment had no effect on EVs release in CECs but increased microglial uptake of CEC-EVs. A Schematic diagram of EVs isolation from conditioned media. B Size distribution of EVs in 2 K, 10 K and 100 K pellets. C Total protein concentrations of 2 K, 10 K and 100 K pellets derived from control group and LPS group. D 2 K, 10 K and 100 K pellets were blotted for the exosomal markers CD63 and syntenin, and for the endoplasmic reticulum marker GP96 and Calnexin. E Flow charts for the EVs purification procedure based on sucrose density gradient centrifugation. F Western blot for exosomal markers CD63, syntenin and Calnexin in different sucrose gradient fractions. G Representative imaging distribution of the DiR-labeled CEC-EVs in different organs, including brain, heart, liver, spleen, lung, and kidney. H CEC-EVs can cross the blood-brain barrier and neuroinflammatory markedly enhanced the incorporation of CEC-EVs into microglia. I Transwell co-culture system. J LPS treatment increased microglial uptake of CEC-EVs. The lipid membrane of CECs was stained with PKH26 red fluorescent dye and the cells were co-cultured with BV2 microglial cells stained with DIO in a Transwell. All data are present as means ± SD (n = 3). Unpaired Student’s t- test. ns not significant.
Fig. 1 LPS treatment had no effect on EVs release in CECs but increased microglial uptake of CEC-EVs. A Schematic diagram of EVs isolation from conditioned media. B Size distribution of EVs in 2 K, 10 K and 100 K pellets. C Total protein concentrations of 2 K, 10 K and 100 K pellets derived from control group and LPS group. D 2 K, 10 K and 100 K pellets were blotted for the exosomal markers CD63 and syntenin, and for the endoplasmic reticulum marker GP96 and Calnexin. E Flow charts for the EVs purification procedure based on sucrose density gradient centrifugation. F Western blot for exosomal markers CD63, syntenin and Calnexin in different sucrose gradient fractions. G Representative imaging distribution of the DiR-labeled CEC-EVs in different organs, including brain, heart, liver, spleen, lung, and kidney. H CEC-EVs can cross the blood-brain barrier and neuroinflammatory markedly enhanced the incorporation of CEC-EVs into microglia. I Transwell co-culture system. J LPS treatment increased microglial uptake of CEC-EVs. The lipid membrane of CECs was stained with PKH26 red fluorescent dye and the cells were co-cultured with BV2 microglial cells stained with DIO in a Transwell. All data are present as means ± SD (n = 3). Unpaired Student’s t- test. ns not significant.CC BY · PubMed Central
Fig. 2 Effect of CEC-EVs on immune responses in microglia. A Heatmap visualization of the expression levels of the differentially expressed genes (DEGs). The colors indicate the expression level, ranging from red (high expression level) to blue (low expression level). The annotation of GO functions (B) and Kyoto Encyclopedia of Genes and Genome (KEGG) (C) pathway analysis of DEGs from microglia after LPS treatment. The annotation of GO functions (D) and KEGG (E) pathway analysis of DEGs from microglia after CEC-EVs treatment. F CEC-EVs alleviates LPS-induced microglial inflammatory responses. One-way ANOVA. G The expression of microglial pro-inflammatory marker (iNOS and CD86) and anti-inflammatory marker (CD206, ARG-1) were examined by western blot. All data are present as means ± SD (n = 3). *p < 0.05, **p < 0.01 compared to control group. ##p < 0.01 compared to LPS group.
Fig. 2 Effect of CEC-EVs on immune responses in microglia. A Heatmap visualization of the expression levels of the differentially expressed genes (DEGs). The colors indicate the expression level, ranging from red (high expression level) to blue (low expression level). The annotation of GO functions (B) and Kyoto Encyclopedia of Genes and Genome (KEGG) (C) pathway analysis of DEGs from microglia after LPS treatment. The annotation of GO functions (D) and KEGG (E) pathway analysis of DEGs from microglia after CEC-EVs treatment. F CEC-EVs alleviates LPS-induced microglial inflammatory responses. One-way ANOVA. G The expression of microglial pro-inflammatory marker (iNOS and CD86) and anti-inflammatory marker (CD206, ARG-1) were examined by western blot. All data are present as means ± SD (n = 3). *p < 0.05, **p < 0.01 compared to control group. ##p < 0.01 compared to LPS group.CC BY · PubMed Central
Fig. 3 miR-672-5p was transferred from CECs to microglia. A The schematic diagram of microglia sequencing analysis after CEC-EVs treatment. B The heat map plot of the upregulated and downregulated miRNAs between microglia treated with CEC-EVs and PBS. C Validation of upregulated genes by qRT-PCR. Unpaired Student’s t test. D qRT-PCR was used to explore the expression of miRNAs including miR-128-3p, miR-672-5p, miR-3058-5p, miR-574-3p and miR-762 in activated microglia treated with EVs. Unpaired Student’s t test. E The EVs secretion inhibitor, GW4869, inhibited miR-672-5p transfer from CECs to microglia. one-way ANOVA. F Inhibition effect of GW4869 on miR-672-5p transfer was determined by qRT-PCR. One-way ANOVA. G miR-672-5p knockdown in CECs and the knockdown efficiency was confirmed by qRT-PCR, one-way ANOVA. Effect of miR-672-5p knockdown in CECs on miR-672-5p expression in CEC-EVs (H) and microglia (I), respectively, one-way ANOVA. All data are present as means ± SD (n = 3). ns not significant, **p < 0.01 compared to control group. ##p < 0.01 compared to miR-NCKD-CEC or miR-NCKD-EVs group.
Fig. 3 miR-672-5p was transferred from CECs to microglia. A The schematic diagram of microglia sequencing analysis after CEC-EVs treatment. B The heat map plot of the upregulated and downregulated miRNAs between microglia treated with CEC-EVs and PBS. C Validation of upregulated genes by qRT-PCR. Unpaired Student’s t test. D qRT-PCR was used to explore the expression of miRNAs including miR-128-3p, miR-672-5p, miR-3058-5p, miR-574-3p and miR-762 in activated microglia treated with EVs. Unpaired Student’s t test. E The EVs secretion inhibitor, GW4869, inhibited miR-672-5p transfer from CECs to microglia. one-way ANOVA. F Inhibition effect of GW4869 on miR-672-5p transfer was determined by qRT-PCR. One-way ANOVA. G miR-672-5p knockdown in CECs and the knockdown efficiency was confirmed by qRT-PCR, one-way ANOVA. Effect of miR-672-5p knockdown in CECs on miR-672-5p expression in CEC-EVs (H) and microglia (I), respectively, one-way ANOVA. All data are present as means ± SD (n = 3). ns not significant, **p < 0.01 compared to control group. ##p < 0.01 compared to miR-NCKD-CEC or miR-NCKD-EVs group.CC BY · PubMed Central
Fig. 4 miR-672-5p negatively regulated TAB2 expression and inhibited the interaction between TAB2 and TAK1. A Candidate gene targets were predicted by intersecting outputs from four distinct prediction software programs (TargetScan, miRWalk, micro-T, and PITA). B miR-672-5p targets the 3′-UTR of TAB2 with a high conservation. C, D Luciferase activity of the wild-type (TAB2-WT) or mutant (TAB2-Mut) TAB2 3’UTR reporter gene transfected with the miR-672-5p mimics or miR-672-5p-NC (negative control). one-way ANOVA. Effect of the transfection of miR-672-5p mimics on expression level of TAB2 protein (E, F) and mRNA (G). Unpaired Student’s t test. H Effect of the transfection of miR-672-5p mimics on protein expression level of TAK1 and its phosphorylation. I Co-immunoprecipitation (Co-IP) experiments were performed with anti-MYC antibody on microglia cell expressing Flag-TAK1 and MYC-TAB2. J Transfection of miR-672-5p mimics or knockdown TAB2 attenuated the interaction between TAB2 and TAK1. All data are present as means ± SD (n = 3). **p < 0.01 compared to TAB2-WT in miR-672-5p-NC treatment group or miR-672-5p-NC group. ##p < 0.01 compared to TAB2-WT group in miR-672-5p mimic treatment group.
Fig. 4 miR-672-5p negatively regulated TAB2 expression and inhibited the interaction between TAB2 and TAK1. A Candidate gene targets were predicted by intersecting outputs from four distinct prediction software programs (TargetScan, miRWalk, micro-T, and PITA). B miR-672-5p targets the 3′-UTR of TAB2 with a high conservation. C, D Luciferase activity of the wild-type (TAB2-WT) or mutant (TAB2-Mut) TAB2 3’UTR reporter gene transfected with the miR-672-5p mimics or miR-672-5p-NC (negative control). one-way ANOVA. Effect of the transfection of miR-672-5p mimics on expression level of TAB2 protein (E, F) and mRNA (G). Unpaired Student’s t test. H Effect of the transfection of miR-672-5p mimics on protein expression level of TAK1 and its phosphorylation. I Co-immunoprecipitation (Co-IP) experiments were performed with anti-MYC antibody on microglia cell expressing Flag-TAK1 and MYC-TAB2. J Transfection of miR-672-5p mimics or knockdown TAB2 attenuated the interaction between TAB2 and TAK1. All data are present as means ± SD (n = 3). **p < 0.01 compared to TAB2-WT in miR-672-5p-NC treatment group or miR-672-5p-NC group. ##p < 0.01 compared to TAB2-WT group in miR-672-5p mimic treatment group.CC BY · PubMed Central
Fig. 5 CEC-EVs-derived miR-672-5p regulated interaction between TAB2 and TAK1 and suppressed NFκB activation in microglia. A Effect of the CEC-EVs-derived miR-672-5p on protein expression level of TAB2, TAK1 and p-TAK1. B CEC-EVs-derived miR-672-5p attenuated the interaction between TAB2 and TAK1. C Schematic diagram of the of in situ proximity ligation assay (PLA) in microglia cells of TAB2 and TAK1. D PLA confirms that CEC-EVs-derived miR-672-5p inhibited the interaction between TAB2 and TAK1. CEC-EVs-derived miR-672-5p promoted the protein expression of p-IKKβ (E) and NFκB (F, G) nuclear translocation. H Representative images of immunofluorescence assays of NFκB in vitro. I CEC-EVs-derived miR-672-5p suppressed the activity of NFκB. All data are present as means ± SD (n = 3). One-way ANOVA. **p < 0.01 compared to Control group. #p < 0.05, ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group.
Fig. 5 CEC-EVs-derived miR-672-5p regulated interaction between TAB2 and TAK1 and suppressed NFκB activation in microglia. A Effect of the CEC-EVs-derived miR-672-5p on protein expression level of TAB2, TAK1 and p-TAK1. B CEC-EVs-derived miR-672-5p attenuated the interaction between TAB2 and TAK1. C Schematic diagram of the of in situ proximity ligation assay (PLA) in microglia cells of TAB2 and TAK1. D PLA confirms that CEC-EVs-derived miR-672-5p inhibited the interaction between TAB2 and TAK1. CEC-EVs-derived miR-672-5p promoted the protein expression of p-IKKβ (E) and NFκB (F, G) nuclear translocation. H Representative images of immunofluorescence assays of NFκB in vitro. I CEC-EVs-derived miR-672-5p suppressed the activity of NFκB. All data are present as means ± SD (n = 3). One-way ANOVA. **p < 0.01 compared to Control group. #p < 0.05, ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group.CC BY · PubMed Central
Fig. 6 CEC-EVs-derived miR-672-5p regulated interaction between TAB2 and TAK1 and suppressed NFκB activation in vivo. A Schematic diagram of the of CEC-EVs in vivo experimental study. B Effect of the CEC-EVs-derived miR-672-5p on protein expression level of TAB2, TAK1 and p-TAK1 in vivo. C PLA confirms that CEC-EVs-derived miR-672-5p inhibited the interaction between TAB2 and TAK1. D Representative western blots of p-IKKβ, IKKβ, p-IκBα, IκBα, NFκB. Statistical graphs of protein expression of p-IKKβ (E), p-IκBα (F), NFκB (G). H, I CEC-EVs-derived miR-672-5p promoted NFκB nuclear translocation. J Representative images of immunofluorescence assays of NFκB in vivo. All data are present as means ± SD (n = 6). One-way ANOVA. **p < 0.01 compared to Control group. ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group.
Fig. 6 CEC-EVs-derived miR-672-5p regulated interaction between TAB2 and TAK1 and suppressed NFκB activation in vivo. A Schematic diagram of the of CEC-EVs in vivo experimental study. B Effect of the CEC-EVs-derived miR-672-5p on protein expression level of TAB2, TAK1 and p-TAK1 in vivo. C PLA confirms that CEC-EVs-derived miR-672-5p inhibited the interaction between TAB2 and TAK1. D Representative western blots of p-IKKβ, IKKβ, p-IκBα, IκBα, NFκB. Statistical graphs of protein expression of p-IKKβ (E), p-IκBα (F), NFκB (G). H, I CEC-EVs-derived miR-672-5p promoted NFκB nuclear translocation. J Representative images of immunofluorescence assays of NFκB in vivo. All data are present as means ± SD (n = 6). One-way ANOVA. **p < 0.01 compared to Control group. ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group.CC BY · PubMed Central
Fig. 7 CEC-EVs-derived miR-672-5p promoted autophagy and suppressed NLRP3 inflammasome activation. A CEC-EVs-derived miR-672-5p enhances LC3II, Beclin1 level and decreases SQSTM1/p62 expression. B–D Statistical graphs of protein expression of LC3II, Beclin1 and SQSTM1/p62. E Immunofluorescence staining of microglial cells transfected with mRFP-GFP-LC3 adenovirus. F, G Calculated numbers of autophagosome (GFP+ RFP+ yellow puncta) and autolysosome (red puncta) numbers. All data are present as means ± SD (n = 3). One-way ANOVA. **p < 0.01 compared to Control group. ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group. H, I Chloroquine (CQ) was used to evaluate the effects of CEC-EVs treatment or LPS treatment on LC3II. CEC-EVs-derived miR-672-5p alleviates LPS-induced microglial inflammatory responses (J) and activation (K). All data are present as means ± SD (n = 6). One-way ANOVA. *p < 0.05, **p < 0.01 compared to CQ− group. ##p < 0.01 compared to CQ+ group.
Fig. 7 CEC-EVs-derived miR-672-5p promoted autophagy and suppressed NLRP3 inflammasome activation. A CEC-EVs-derived miR-672-5p enhances LC3II, Beclin1 level and decreases SQSTM1/p62 expression. B–D Statistical graphs of protein expression of LC3II, Beclin1 and SQSTM1/p62. E Immunofluorescence staining of microglial cells transfected with mRFP-GFP-LC3 adenovirus. F, G Calculated numbers of autophagosome (GFP+ RFP+ yellow puncta) and autolysosome (red puncta) numbers. All data are present as means ± SD (n = 3). One-way ANOVA. **p < 0.01 compared to Control group. ##p < 0.01 compared to LPS group. &&p < 0.01 compared to LPS + miR-NCKD-EVs group. H, I Chloroquine (CQ) was used to evaluate the effects of CEC-EVs treatment or LPS treatment on LC3II. CEC-EVs-derived miR-672-5p alleviates LPS-induced microglial inflammatory responses (J) and activation (K). All data are present as means ± SD (n = 6). One-way ANOVA. *p < 0.05, **p < 0.01 compared to CQ− group. ##p < 0.01 compared to CQ+ group.CC BY · PubMed Central
Fig. 8 The neuroprotective effects of CEC-EVs in LPS-induced behavioral deficits in mice. A Representative traces indicating the paths of the mice in the space exploration and orientation navigation test. B CEC-EVs treatment reduced the time spent to find the submerged platform. CEC-EVs treatment enhanced the number of crossing (C) and reduced the time spent on exploring the quadrant that initially contained the platform (D). E Representative heat maps showing EPM results. CEC-EVs treatment increased number of open arm entries (F) and time spent in the open arm of the EPM test (G). H CEC-EVs treatment increased sucrose preference in the SPT. I CEC-EVs treatment decreased immobility time in the FST. All data are present as means ± SD (n = 12). One-way ANOVA. **p < 0.01 compared to Control group. #p < 0.05, ##p < 0.01 compared to LPS group. &p < 0.05, &&p < 0.01 compared to LPS + miR-NCKD-EVs group.
Fig. 8 The neuroprotective effects of CEC-EVs in LPS-induced behavioral deficits in mice. A Representative traces indicating the paths of the mice in the space exploration and orientation navigation test. B CEC-EVs treatment reduced the time spent to find the submerged platform. CEC-EVs treatment enhanced the number of crossing (C) and reduced the time spent on exploring the quadrant that initially contained the platform (D). E Representative heat maps showing EPM results. CEC-EVs treatment increased number of open arm entries (F) and time spent in the open arm of the EPM test (G). H CEC-EVs treatment increased sucrose preference in the SPT. I CEC-EVs treatment decreased immobility time in the FST. All data are present as means ± SD (n = 12). One-way ANOVA. **p < 0.01 compared to Control group. #p < 0.05, ##p < 0.01 compared to LPS group. &p < 0.05, &&p < 0.01 compared to LPS + miR-NCKD-EVs group.CC BY · PubMed Central

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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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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