Abstract
Background and Objectives Progranulin (PGRN) is an important immune regulatory molecule in several immune-mediated diseases. The objective of this study is to investigate the role of PGRN in uveitis and its counterpart, experimental autoimmune uveitis (EAU), and experimental autoimmune encephalomyelitis (EAE).
Methods Serum PGRN levels in patients with Behcet disease (BD) or Vogt-Koyanagi-Harada (VKH) disease and normal controls were measured by ELISA. EAE and EAU were induced in B10RIII, wild-type, and PGRN−/− mice to evaluate the effect of PGRN on the development of these 2 immune-mediated disease models. The local and systemic immunologic alterations were detected by ELISA, flow cytometry, and real-time PCR. RNA sequencing was performed to identify the hub genes and key signaling pathway.
Results A significantly decreased PGRN expression was observed in patients with active BD and active VKH. Recombinant PGRN significantly reduced EAU severity in association with a decreased frequency of Th17 and Th1 cells. PGRN−/− mice developed an exacerbated EAU and EAE in association with strikingly increased frequency of Th1 and Th17 cells and reduced frequency of regulatory T (Treg) cells. In vitro studies revealed that rPGRN could inhibit IRBP161–180-specific Th1 and Th17 cell response and promote Treg cell expansion. It promoted non–antigen-specific Treg cell polarization from naive CD4+ T cells in association with increased STAT5 phosphorylation. Using RAN sequencing, we identified 5 shared hub genes including Tnf, Il6, Il1b, Cxcl2, and Ccl2 and the most significantly enriched MAPK and tumor necrosis factor signaling pathway in PGRN−/− EAU mice. The aggravated EAE activity in PGRN−/− mice was associated with a skew from M2 to M1 macrophages.
Discussion Our results collectively reveal an important protective role of PGRN in EAU and EAE. These studies suggest that PGRN could serve as an immunoregulatory target in the study of prevention and treatment for the Th1/Th17-mediated diseases.
Glossary
- Arg-1=
- arginase 1;
- BD=
- Behcet disease;
- DEGs=
- differentially expressed genes;
- EAE=
- experimental autoimmune encephalomyelitis;
- EAU=
- experimental autoimmune uveitis;
- ERK=
- extracellular signal-regulated kinase;
- GO=
- gene ontology;
- GSEA=
- gene set enrichment analysis;
- IFN=
- interferon;
- IL=
- interleukin;
- iNOS=
- inducible nitric oxide synthase;
- JNK=
- Jun N-terminal kinase;
- KEGG=
- Kyoto Encyclopedia of Genes and Genomes;
- MAPK=
- mitogen-activated protein kinase;
- MCP=
- monocyte chemoattractant protein;
- mRNA=
- messenger RNA;
- MS=
- multiple sclerosis;
- PGRN=
- progranulin;
- RNA-seq=
- RNA sequencing;
- RT-PCR=
- real-time PCR;
- Th=
- T helper;
- TNF=
- tumor necrosis factor;
- Treg=
- regulatory T;
- VKH=
- Vogt-Koyanagi-Harada;
- WT=
- wild type
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this study and should therefore be regarded as co–first authors.
The Article Processing Charge was funded by the authors.
- Received June 15, 2021.
- Accepted in final form November 24, 2021.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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