PEDF alleviates autoimmune uveitis and reprograms Treg metabolism
4 affiliations
- 1Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute, School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300071 China
- 2College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071 China
- 3Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260 China
- 4Tianjin Key Laboratory of Ophthalmology and Visual Science, Clinical College of Ophthalmology, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin Medical University, Nankai University Affiliate Tianjin Eye Hospital, Tianjin, China
Abstract
T cell–mediated autoimmune diseases remain difficult to manage owing to limited options and adverse effects of current immunosuppressants; safer, tolerance-preserving approaches are needed. We identify pigment epithelium-derived factor (PEDF) as an endogenous regulator of ocular immunity with therapeutic potential. PEDF expression was induced during autoimmune uveitis (AU) in patients and during experimental autoimmune uveitis (EAU) progression, suggesting an endogenous compensatory response to inflammatory stress. Loss of PEDF did not substantially alter early peripheral immune activation but impaired inflammatory control during established disease, leading to persistent retinal inflammation and reduced Foxp3⁺ regulatory T (Treg) responses. Conversely, intravitreal administration of recombinant PEDF enhanced Treg responses and promoted inflammatory resolution, thereby alleviating EAU severity. Mechanistically, we delineate a PEDF–ATGL–DHA–PPARγ axis that reprograms Treg metabolism: PEDF activates adipose triglyceride lipase (ATGL) to mobilize docosahexaenoic acid (DHA), enhancing mitochondrial oxidative metabolism and stabilizing Foxp3 via PPARγ. Together, these findings establish PEDF as a physiological checkpoint that links lipid utilization to immune tolerance, and demonstrate a metabolism-centered, cytokine-independent strategy to reinforce Treg stability in vivo. Having shown efficacy in an ocular model of T cell–driven autoimmunity, PEDF-based immunometabolic modulation defines a broadly applicable strategy for restoring immune tolerance across T cell–mediated autoimmune diseases.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12974-026-03980-3.
Related
- A Self-Developed IL-6Rα Nanobody Alleviates Experimental Autoimmune Uveitis by Inhibiting Th1 and Th17 Cells
- HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune uveoretinitis
- The PGC-1α Gly482Ser rs8192678 SNP reprograms oxidative metabolism to favor energy storage in females
- Re-Du-Ning Alleviates Airway-Intestinal Inflammation of COPD Rats by Regulating Glycerophospholipid Metabolism and Modulating Gut Microbiome
- Sotagliflozin Reprograms Hepatic Lipid Metabolism and Attenuates Atherosclerosis Beyond Empagliflozin in CKM Mice
BibTeX
@article{zhang2026pedf,
title = {{PEDF alleviates autoimmune uveitis and reprograms Treg metabolism}},
author = {Zhihui Zhang and Yongtao Li and Huan Li and Mi Zhang and Zhen Qian and Baiyi Li and Nu Chen and Jiawei Wang and Xuexue Cui and Mengjuan Zhang and Song Zhang and Lai Wei and Xiaomin Zhang},
journal = {Journal of Neuroinflammation},
year = {2026},
month = jul,
doi = {10.1186/s12974-026-03980-3},
url = {https://doi.org/10.1186/s12974-026-03980-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - PEDF alleviates autoimmune uveitis and reprograms Treg metabolism
AU - Zhihui Zhang
AU - Yongtao Li
AU - Huan Li
AU - Mi Zhang
AU - Zhen Qian
AU - Baiyi Li
AU - Nu Chen
AU - Jiawei Wang
AU - Xuexue Cui
AU - Mengjuan Zhang
AU - Song Zhang
AU - Lai Wei
AU - Xiaomin Zhang
PY - 2026
DA - 2026/07/31
JO - Journal of Neuroinflammation
DO - 10.1186/s12974-026-03980-3
UR - https://doi.org/10.1186/s12974-026-03980-3
AB - T cell–mediated autoimmune diseases remain difficult to manage owing to limited options and adverse effects of current immunosuppressants; safer, tolerance-preserving approaches are needed. We identify pigment epithelium-derived factor (PEDF) as an endogenous regulator of ocular immunity with therapeutic potential. PEDF expression was induced during autoimmune uveitis (AU) in patients and during experimental autoimmune uveitis (EAU) progression, suggesting an endogenous compensatory response to inflammatory stress. Loss of PEDF did not substantially alter early peripheral immune activation but impaired inflammatory control during established disease, leading to persistent retinal inflammation and reduced Foxp3⁺ regulatory T (Treg) responses. Conversely, intravitreal administration of recombinant PEDF enhanced Treg responses and promoted inflammatory resolution, thereby alleviating EAU severity. Mechanistically, we delineate a PEDF–ATGL–DHA–PPARγ axis that reprograms Treg metabolism: PEDF activates adipose triglyceride lipase (ATGL) to mobilize docosahexaenoic acid (DHA), enhancing mitochondrial oxidative metabolism and stabilizing Foxp3 via PPARγ. Together, these findings establish PEDF as a physiological checkpoint that links lipid utilization to immune tolerance, and demonstrate a metabolism-centered, cytokine-independent strategy to reinforce Treg stability in vivo. Having shown efficacy in an ocular model of T cell–driven autoimmunity, PEDF-based immunometabolic modulation defines a broadly applicable strategy for restoring immune tolerance across T cell–mediated autoimmune diseases. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12974-026-03980-3.
SN - 1742-2094
ER -