Drainage of inflammatory macromolecules from brain to periphery targets the liver for macrophage infiltration

Abstract

Many brain pathologies are associated with liver damage, but a direct link has long remained elusive. Here, we establish a new paradigm for interrogating brain-periphery interactions by leveraging zebrafish for its unparalleled access to the intact whole animal for in vivo analysis in real time after triggering focal brain inflammation. Using traceable lipopolysaccharides (LPS), we reveal that drainage of these inflammatory macromolecules from the brain led to a strikingly robust peripheral infiltration of macrophages into the liver independent of Kupffer cells. We further demonstrate that this macrophage recruitment requires signaling from the cytokine IL-34 and Toll-like receptor adaptor MyD88, and occurs in coordination with neutrophils. These results highlight the possibility for circulation of brain-derived substances to serve as a rapid mode of communication from brain to the liver. Understanding how the brain engages the periphery at times of danger may offer new perspectives for detecting and treating brain pathologies.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Linlin Yang

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5602-4157
  2. Jessica A Jiménez

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alison M Earley

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1889-9221
  4. Victoria Hamlin

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Victoria Kwon

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Cameron T Dixon

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Celia E Shiau

    Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    shiauce@unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9347-9158

Funding

National Institutes of Health (1R35GM124719)

  • Celia E Shiau

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#16-160 and #19-132) of the UNC Chapel Hill.

Reviewing Editor

  1. Michel Bagnat, Duke University, United States

Version history

  1. Received: April 23, 2020
  2. Accepted: July 27, 2020
  3. Accepted Manuscript published: July 31, 2020 (version 1)
  4. Version of Record published: August 18, 2020 (version 2)
  5. Version of Record updated: September 7, 2020 (version 3)

Copyright

© 2020, Yang 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

  • 3,083
    Page views
  • 350
    Downloads
  • 7
    Citations

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

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

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

  1. Linlin Yang
  2. Jessica A Jiménez
  3. Alison M Earley
  4. Victoria Hamlin
  5. Victoria Kwon
  6. Cameron T Dixon
  7. Celia E Shiau
(2020)
Drainage of inflammatory macromolecules from brain to periphery targets the liver for macrophage infiltration
eLife 9:e58191.
https://doi.org/10.7554/eLife.58191

Further reading

    1. Immunology and Inflammation
    Atomu Yamaguchi, Noriaki Maeshige ... Hidemi Fujino
    Research Article

    The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Huiyun Lyu, Guohua Yuan ... Yan Shi
    Research Article

    Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.