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

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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.

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All data needed to evaluate the conclusions of the paper are present in the main text and Supplementary Materials.

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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.

"This ORCID iD identifies the author of this article:" 0000-0002-7329-2812
Mary J Mattapallil

NEI, NIH, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Reiko Horai

NEI, NIH, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Yingyos Jittayasothorn

NEI, NIH, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Arnav P Modi

School of Optometry, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
H Nida Sen

NEI, NIH, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-5329-7907
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.

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.