1. Immunology and Inflammation
Download icon

MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway

Research Article
  • Cited 6
  • Views 1,914
  • Annotations
Cite this article as: eLife 2019;8:e41159 doi: 10.7554/eLife.41159

Abstract

MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoring miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially of hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 down-regulated the phosphorylation (Tyr705) of STAT3 and thereby removed the negative regulation of STAT3 on IFN-signaling. While STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122-RTKs/STAT3-IRF1-IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge about miR-122's function and have important implications for treating hepatitis viruses.

Article and author information

Author details

  1. Hui Xu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shi-Jun Xu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Shu-Juan Xie

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yin Zhang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jian-Hua Yang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3863-2786
  6. Wei-Qi Zhang

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Man-Ni Zheng

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Hui Zhou

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Liang-Hu Qu

    School of Life Sciences, Sun Yat-sen University, Guangzhou, China
    For correspondence
    lssqlh@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3657-2863

Funding

National Natural Science Foundation of China (31200593)

  • Hui Xu

National Natural Science Foundation of China (31230042)

  • Liang-Hu Qu

National Natural Science Foundation of China (31471223)

  • Liang-Hu Qu

National Natural Science Foundation of China (31671349)

  • Liang-Hu Qu

Natural Science Foundation of Guangdong Province (2014A030313163)

  • Hui Xu

National Basic Research Program of China (2011CB811300)

  • Liang-Hu Qu

National Key R&D Program of China (2017YFA0504400)

  • Jian-Hua Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Publication history

  1. Received: August 16, 2018
  2. Accepted: February 7, 2019
  3. Accepted Manuscript published: February 8, 2019 (version 1)
  4. Version of Record published: February 25, 2019 (version 2)

Copyright

© 2019, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,914
    Page views
  • 346
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Immunology and Inflammation
    Julie Y Zhou et al.
    Research Article

    Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.

    1. Cancer Biology
    2. Immunology and Inflammation
    Giulia Vanoni et al.
    Research Article Updated

    Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in endothelial cells (ECs) in vitro, mainly in a contact-dependent manner through the tumor necrosis factor receptor- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP–EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response.