1. Immunology and Inflammation
Download icon

A novel role for lipoxin A4 in driving a lymph node-eye axis that controls autoimmunity to the neuroretina

  1. Jessica Wei
  2. Mary J Mattapallil
  3. Reiko Horai
  4. Yingyos Jittayasothorn
  5. Arnav P Modi
  6. H Nida Sen
  7. Karsten Gronert  Is a corresponding author
  8. Rachel R Caspi  Is a corresponding author
  1. University of California, Berkeley, United States
  2. NIH, United States
Research Article
  • Cited 2
  • Views 658
  • Annotations
Cite this article as: eLife 2020;9:e51102 doi: 10.7554/eLife.51102

Abstract

The eicosanoid lipoxin A4 (LXA4) has emerging roles in lymphocyte-driven diseases. We identified reduced LXA4 levels in posterior segment uveitis patients and investigated the role of LXA4 in the pathogenesis of experimental autoimmune uveitis (EAU). Immunization for EAU with a retinal self-antigen caused selective downregulation of LXA4 in lymph nodes draining the site of immunization, while at the same time amplifying LXA4 in the inflamed target tissue. T cell effector function, migration and glycolytic responses were amplified in LXA4-deficient mice, which correlated with more severe pathology, whereas LXA4 treatment attenuated disease. In vivo deletion or supplementation of LXA4 identified modulation of CC-chemokine receptor 7 (CCR7) and sphingosine 1- phosphate receptor-1 (S1PR1) expression and glucose metabolism in CD4+ T cells as potential mechanisms for LXA4 regulation of T cell effector function and trafficking. Our results demonstrate the intrinsic lymph node LXA4 pathway as a significant checkpoint in the development and severity of adaptive immunity.

Article and author information

Author details

  1. Jessica Wei

    Vision Science Program, School of Optometry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7329-2812

  2. Mary J Mattapallil

    NEI, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Reiko Horai

    NEI, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Yingyos Jittayasothorn

    NEI, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Arnav P Modi

    School of Optometry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. H Nida Sen

    NEI, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Karsten Gronert

    Vision Science Program, School of Optometry, University of California, Berkeley, Berkeley, United States
    For correspondence
    kgronert@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5329-7907

  8. Rachel R Caspi

    Lab. Immunol., NEI, NIH, Bethesda, United States
    For correspondence
    caspir@nei.nih.gov
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Eye Institute (EY026082)

  • Karsten Gronert

National Eye Institute (EY000184)

  • Rachel R Caspi

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

Ethics

Animal experimentation: All experimental procedures were approved by the Animal Care and Use program at University of California, Berkeley, and the National Eye Institute at the National Institutes of Health.(protocol AUP-2016-04-8691-1),

Human subjects: Male and female patients ages 30 - 76 with clinical diagnosis of non-infectious posterior segment uveitis were enrolled in the National Eye Institute protocol number 16-EI-0046. Healthy controls were NIH blood bank donors of both sexes with a similar age range. Serum samples were obtained from male and female patients ages 30 - 76 with clinical diagnosis of non-infectious posterior uveitis, healthy controls were NIH blood bank donors of both sexes with a similar age range whose samples were de-identified and sent to the lab. Patients were enrolled from May 2017 to July 2018 under a clinical research protocol 428 (NCT02656381), approved by the institutional review board of the National Institutes of Health. Informed consent (including publishing language as required by NIH IRB) were obtained from all subjects. The study adhered to the tenets of the Declaration of Helsinki.

Reviewing Editor

  1. Lois Smith, Boston Children's Hospital/Harvard Medical School, United States

Publication history

  1. Received: August 15, 2019
  2. Accepted: February 29, 2020
  3. Accepted Manuscript published: March 2, 2020 (version 1)
  4. Version of Record published: March 10, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 658
    Page views
  • 82
    Downloads
  • 2
    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)

Categories and tags

Research organisms

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Mapping immune variation and var gene switching in naive hosts infected with Plasmodium falciparum

    Kathryn Milne et al.
    Research Article

    Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates

    Yasmine Issah et al.
    Research Article

    Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-à-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, Bmal1, in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.

    1. Cell Biology
    2. Immunology and Inflammation

    Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism

    Leonie Zeitler et al.
    Research Article

    Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologues in snake venoms (LAAO, L-amino acid oxidases), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell productive gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.