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Isolation and Profiling of MicroRNA-containing Exosomes from Human Bile
Published on: June 13, 2016
M1 macrophage-derived exosomes promote autoimmune liver injury by transferring long noncoding RNA H19 to hepatocytes
Yongting Zhang1, Liang Hong1, Xuehui Li1
1State Key Laboratory for Diagnosis & Treatment of Infectious Diseases National Clinical Research Center for Infectious Disease Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China.
Abstract:
Exosomes mediate intercellular communication by transmitting active molecules. The function of long noncoding RNA (lncRNA) H19 in autoimmune liver injury is unclear. Concanavalin A (ConA)-induced liver injury is well-characterized immune-mediated hepatitis. Here, we showed that lncRNA H19 expression was increased in the liver after ConA treatment, accompanied by increased exosome secretion. Moreover, injection of AAV-H19 aggravated ConA-induced hepatitis, with an increase in hepatocyte apoptosis. However, GW4869, an exosome inhibitor, alleviated ConA-induced liver injury and inhibited the upregulation of lncRNA H19. Intriguingly, lncRNA H19 expression in the liver was significantly downregulated, after macrophage depletion. Importantly, the lncRNA H19 was primarily expressed in type I macrophage (M1) and encapsulated in M1-derived exosomes. Furthermore, H19 was transported from M1 to hepatocytes via exosomes, and exosomal H19 dramatically induced hepatocytes apoptosis both in vitro and vivo. Mechanistically, H19 upregulated the transcription of hypoxia-inducible factor-1 alpha (HIF-1α), which accumulated in the cytoplasm and mediated hepatocyte apoptosis by upregulating p53. M1-derived exosomal lncRNA H19 plays a pivotal role in ConA-induced hepatitis through the HIF-1α-p53 signaling pathway. These findings identify M1 macrophage-derived exosomal H19 as a novel target for the treatment of autoimmune liver diseases.
Insights
Macrophage-derived exosomes carrying the H19 long noncoding RNA worsen autoimmune liver injury by inducing hepatocyte apoptosis. Inhibiting H19 or exosomes may treat this condition.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- Exosomes facilitate intercellular communication via active molecule transmission.
- The role of long noncoding RNA (lncRNA) H19 in autoimmune liver injury remains largely unknown.
- Concanavalin A (ConA)-induced liver injury is a recognized model of immune-mediated hepatitis.
Purpose of the Study:
- To investigate the function of lncRNA H19 in ConA-induced autoimmune liver injury.
- To elucidate the mechanism by which H19 contributes to liver damage.
- To identify potential therapeutic targets for autoimmune liver diseases.
Main Methods:
- Concanavalin A (ConA) administration in a mouse model.
- Assessment of lncRNA H19 expression and exosome secretion.
- Inhibition of exosomes using GW4869.
- Macrophage depletion studies.
- In vitro and in vivo experiments assessing hepatocyte apoptosis.
- Analysis of the HIF-1α-p53 signaling pathway.
Main Results:
- lncRNA H19 expression and exosome secretion increased in ConA-induced liver injury.
- Exogenous H19 aggravated liver injury and hepatocyte apoptosis, while exosome inhibition alleviated it.
- H19 was primarily expressed in M1 macrophages and packaged into M1-derived exosomes.
- Exosomal H19 transferred from M1 macrophages to hepatocytes, inducing apoptosis via the HIF-1α-p53 pathway.
Conclusions:
- M1 macrophage-derived exosomal lncRNA H19 is a key mediator of ConA-induced hepatitis.
- H19 promotes hepatocyte apoptosis through the HIF-1α-p53 signaling cascade.
- M1 macrophage-derived exosomal H19 represents a novel therapeutic target for autoimmune liver diseases.
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