PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy

Zhiyu Peng; Zhiyu Peng; Zhiyu Peng; Zhiyu Peng; Rui Huang; Rui Huang; Rui Huang; Lu Gan; Lu Gan; Lu Gan; Jinghan Wang; Jinghan Wang; Jinghan Wang; Xiaofeng Li; Xiaofeng Li; Xiaofeng Li; Jie Ding; Jie Ding; Jie Ding; Yinan Han; Yinan Han; Yinan Han; Jihong Wu; Jihong Wu; Jihong Wu; Kang Xue; Kang Xue; Kang Xue; Jie Guo; Jie Guo; Jie Guo; Rui Zhang; Jiang Qian; Ruiqi Ma; Ruiqi Ma; Ruiqi Ma

doi:10.3389/fimmu.2025.1537365

Frontiers in Immunology (Feb 2025)

PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy

Zhiyu Peng,
Zhiyu Peng,
Zhiyu Peng,
Zhiyu Peng,
Rui Huang,
Rui Huang,
Rui Huang,
Lu Gan,
Lu Gan,
Lu Gan,
Jinghan Wang,
Jinghan Wang,
Jinghan Wang,
Xiaofeng Li,
Xiaofeng Li,
Xiaofeng Li,
Jie Ding,
Jie Ding,
Jie Ding,
Yinan Han,
Yinan Han,
Yinan Han,
Jihong Wu,
Jihong Wu,
Jihong Wu,
Kang Xue,
Kang Xue,
Kang Xue,
Jie Guo,
Jie Guo,
Jie Guo,
Rui Zhang,
Jiang Qian,
Ruiqi Ma,
Ruiqi Ma,
Ruiqi Ma

Affiliations

Zhiyu Peng: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Zhiyu Peng: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Zhiyu Peng: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Zhiyu Peng: Department of Ophthalmology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Rui Huang: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Rui Huang: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Rui Huang: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Lu Gan: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Lu Gan: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Lu Gan: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Jinghan Wang: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Jinghan Wang: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Jinghan Wang: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Xiaofeng Li: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Xiaofeng Li: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Xiaofeng Li: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Jie Ding: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Jie Ding: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Jie Ding: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Yinan Han: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Yinan Han: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Yinan Han: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Jihong Wu: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Jihong Wu: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Jihong Wu: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Kang Xue: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Kang Xue: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Kang Xue: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Jie Guo: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Jie Guo: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Jie Guo: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China
Rui Zhang: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Jiang Qian: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Ruiqi Ma: Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, China
Ruiqi Ma: Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
Ruiqi Ma: NHC Key Laboratory of Myopia, Fudan University, Shanghai, China

DOI: https://doi.org/10.3389/fimmu.2025.1537365
Journal volume & issue: Vol. 16

Abstract

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ObjectivesTransforming 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.MethodsOrbital 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.ResultsOrbital 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 the orbital tissue. Targeting PDK2 decreased IL11 expression to suppress fibrosis. In vivo experiment confirmed anti-fibrotic effect of inhibition of glycolysis.ConclusionsPDK2-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.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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