Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy
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Molecular Medicine
RESEARCH ARTICLE
Open Access
Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy Ling Wang1, Yinghao Wang2 and Jun Quan1*
Abstract Background: Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrosis. We previously demonstrated that exosomes derived from natural killer (NK) cells (NK-Exo) attenuated TGF-β1-induced HSC activation. Herein, this study was designed to investigate the mechanism underlying the action of NK-Exo. Methods: NK-Exo was isolated from NK-92MI cells and then administered into TGF-β1-treated LX-2 (human HSC line) cells. MiR-223 expression in NK-Exo was downregulated by transfecting NK-92MI cells with miR-223 inhibitor followed by exosome isolation. The HSC activation was evaluated by determining cell proliferation using CCK-8 assay and measuring the protein levels of α-SMA and CoL1A1 using western blot in LX-2 cells. The expression of miR-223 was detected by qRT-PCR. The interaction between miR-223 and ATG7 was analyzed by a dual-luciferase activity assay. The autophagy was evaluated by measuring the autophagy-related proteins using western blot. Results: miR-223 was highly expressed in NK-Exo and inhibition of miR-223 expression in NK-Exo abrogated the inhibitory effect of NK-Exo on TGF-β-induced HSC activation. ATG7 was confirmed as a direct target of miR-223. Furthermore, treatment with the autophagy activator rapamycin and ATG7 overexpression in LX-2 cells abolished the HSC activation-suppressive effect of NK-Exo. Conclusion: NK-Exo attenuated TGF-β-induced HSC activation by transferring miR-223 that inhibited autophagy via targeting ATG7. Keywords: Hepatic stellate cell activation, Natural killer cell, Exosome, miR-223, Autophagy
Background Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrosis that can eventually lead to cirrhosis, liver failure, and even liver cancer (Higashi et al. 2017; Parola and Pinzani 2019). As such, effective therapeutic strategies for inhibiting HSC activation are urgently needed to reverse liver fibrosis. Exosomes are nano-sized membrane vesicles (30–150 nm in diameter) that can be released from various cell types (Chen et al. 2020). Natural killer (NK) cells are important effector cells in many innate immune processes and play an * Correspondence: [email protected] 1 Department of Infectious Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha 410008, Hunan, China Full list of author information is available at the end of the article
important regulatory role in HSC activation (Fasbender et al. 2016; Foley et al. 2011). NK cells can influence the biological functions of recipient cells through secretion of exosomes (Shoae-Hassani et al. 2017; Neviani et al. 2019). Our group has previously demonstrated that exosomes derived from NK cells (NK-Exo) inhibited TGFβ1-induced HSC activation in HSC-LX-2 cells and carbon tetrachloride (CCl4)-induced liver fibrosis in BALB/ c mice (Wang et al. 2020
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