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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1537365
This article is part of the Research Topic Intestinal microenvironment and autoimmune diseases View all articles

PDK2-enhanced Glycolysis Aggravates Fibrosis via IL11 Signaling Pathway in Graves' Orbitopathy

Provisionally accepted
Zhiyu Peng Zhiyu Peng 1,2Rui Huang Rui Huang 1*Lu Gan Lu Gan 1*Jinghan Wang Jinghan Wang 1Xiaofeng Li Xiaofeng Li 1*Jie Ding Jie Ding 1*Yinan Han Yinan Han 1*jihong wu jihong wu 1Kang Xue Kang Xue 1Jie Guo Jie Guo 1*Rui Zhang Rui Zhang 1*Jiang Qian Jiang Qian 1*Ruiqi Ma Ruiqi Ma 1*
  • 1 Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, Shanghai Municipality, China
  • 2 Department of Ophthalmology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

The final, formatted version of the article will be published soon.

    Objectives: Transforming growth factor β1 (TGFβ1)-interleukin 11 (IL11) is a newly found critical signaling pathway in fibrotic diseases such as Graves' orbitopathy (GO). It has now been confirmed that enhanced glycolysis plays a key role in the pathogenesis of GO. However, little is known about the relationship between glycolysis and IL11-mediated fibrosis in GO.This study aimed to identify the relationship between glycolysis and TGFβ1-IL11 signaling pathway and investigate the role of IL11 in glycolysis-facilitated fibrosis in GO.Methods: Orbital connective tissues were collected from GO and control patients. Primary orbital fibroblasts (OFs) were cultured from clinical tissues. Patient-derived xenografts were established via intraorbital transplantation of GO orbital tissue in humanized NCG mice.Protein levels were measured using Capillary Western Immunoassay (WES). Small interfering RNA (siRNA) was used to construct transfected OF strains. Lactate production was measured to assess glycolysis status. Animal models were assessed by T2-weighted magnetic resonance (MR) scan. Immunohistochemistry staining was applied to patients' orbital connective tissues.Results: Orbital connective tissues were collected from GO patients. Immunohistochemical (IHC) staining of GO tissues revealed the phenomenon of pyruvate dehydrogenase kinase 2 (PDK2)enhanced glycolysis and upregulated IL11-IL11Rα pathway. In vitro experiments showed successful induction of fibrosis of patient-derived orbital fat/connective tissues which could be alleviated by dichloroacetic acid (DCA). MRI images and analysis of hematoxylin and eosin (HE) and Masson stained section demonstrated enhanced glycolysis in GO facilitating fibrosis of orbital tissue. Targeting PDK2 decreased IL11 expression to suppress fibrosis. In vivo experiment confirmed anti-fibrotic effect of inhibition of glycolysis. Conclusions: PDK2-enhanced glycolysis exacerbates fibrosis via IL11-IL11Rα signaling pathway, shedding light on a potential therapeutic role of metabolic modulators such as DCA in GO treatment.

    Keywords: Glycolysis, Interleukin-11, Transforming Growth Factor beta1, Orbital fibroblast, Graves' orbitopathy

    Received: 30 Nov 2024; Accepted: 27 Jan 2025.

    Copyright: © 2025 Peng, Huang, Gan, Wang, Li, Ding, Han, wu, Xue, Guo, Zhang, Qian and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Rui Huang, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Lu Gan, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Xiaofeng Li, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Jie Ding, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Yinan Han, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Jie Guo, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Rui Zhang, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Jiang Qian, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China
    Ruiqi Ma, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200032, Shanghai Municipality, China

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