Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
Yong He, Robim M. Rodrigues, Xiaolin Wang, Wonhyo Seo, Jing Ma, Seonghwan Hwang, Yaojie Fu, Eszter Trojnár, Csaba Mátyás, Suxian Zhao, Ruixue Ren, Dechun Feng, Pal Pacher, George Kunos, Bin Gao
Yong He, Robim M. Rodrigues, Xiaolin Wang, Wonhyo Seo, Jing Ma, Seonghwan Hwang, Yaojie Fu, Eszter Trojnár, Csaba Mátyás, Suxian Zhao, Ruixue Ren, Dechun Feng, Pal Pacher, George Kunos, Bin Gao
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Research Article Hepatology

Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis

Abstract

Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223–enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223–enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223–enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH.

Authors

Yong He, Robim M. Rodrigues, Xiaolin Wang, Wonhyo Seo, Jing Ma, Seonghwan Hwang, Yaojie Fu, Eszter Trojnár, Csaba Mátyás, Suxian Zhao, Ruixue Ren, Dechun Feng, Pal Pacher, George Kunos, Bin Gao

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Figure 7

Apoe deficiency in immune cells worsens NASH partially due to less transfer of miR-223 to hepatocytes.

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Apoe deficiency in immune cells worsens NASH partially due to less tran...
WT mice were transplanted with WT or Apoe-KO mouse bone marrow (BM). The superscript characters indicate the donor mouse BM. Two months later, these mice were subjected to CD or HFD feeding for 3 months. Serum and liver tissue samples were collected (n = 3 in CD-fed group, n = 9 in HFD-fed group). (A) miR-223 in the liver was measured by RT-qPCR. (B) Serum ALT was measured. (C) Representative images of H&E staining (scale bars: 200 μm), Sirius red staining (scale bars: 200 μm), and α-SMA staining (scale bars: 100 μm) of liver tissue sections are shown. Fibrotic area per field was quantified (bottom). (D) RT-qPCR analyses of several genes in the liver tissues from HFD-fed mice. Values represent means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. Significance was determined by 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (A) and a 2-tailed Student’s t test for comparing 2 groups (B and C).