Dendritic cell‐derived exosomal miR‐3064‐5p inhibits SIRT6/PCSK9 to protect the blood‐brain barrier after subarachnoid hemorrhage

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Abstract

The protection of the blood‐brain barrier (BBB) is the key direction to improving subarachnoid hemorrhage (SAH). Therefore, developing appropriate targeted drugs and therapies has become an urgent task for SAH patients. In this study, we investigated the role of dendritic cells (DCs) exosomal miR‐3064‐5p in repairing the BBB, providing a new basis for treating SAH. We detected the expression of miR‐3064‐5p in exosomes secreted by DCs (DCs‐exo). An SAH rat model was constructed by intravascular perforation and characterized by HE and TUNEL‐IF staining. We found that overexpression of miR‐3064‐5p in SAH rats suppressed iNOS expression and promoted the accumulation of tight junction proteins (Occludin, Claudin‐3, ZO‐1), whereas knockdown of miR‐3064‐5p exerted the opposite effect. Dual‐LUC assay confirmed that miR‐3064‐5p could target and inhibit SIRT6. Knockdown of SIRT6 inhibited inflammatory cytokine (IL‐6, IL‐1β, IFN‐γ, and TGF‐β1) levels and apoptosis. The results of the co‐IP assay showed that SIRT6 interacted with PCSK9, and knockdown of SIRT6 suppressed the expression of PCSK9. Moreover, DCs‐exo reduced brain edema, upregulated miR‐3064‐5p and downregulated SIRT6 and PCSK9 in SAH rats. DCs‐exo reduced inflammatory factors and increased tight junction proteins in SAH rats. Overexpression of miR‐3064‐5p enhanced the protective effect of DCs‐exo, while overexpression of SIRT6 partially counteracted the effect. This study confirmed that DCs could secrete miR‐3064‐5p to ameliorate BBB damage after SAH. Mechanistically, miR‐3064‐5p alleviated BBB damage by targeting and inhibiting SIRT6/PCSk9 signaling pathway.

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The biology, function, and biomedical applications of exosomes

Raghu Kalluri, Valerie LeBleu (2020)

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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Dendritic cell-derived exosomes for cancer therapy.

Jonathan M Pitt, Fabrice André, Sebastian Amigorena … (2016)

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell-dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell-based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.