PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy
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 r...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1537365/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhiyu Peng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-894e16e610e44ef2a41654c946b6edee |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-894e16e610e44ef2a41654c946b6edee2025-08-20T03:12:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15373651537365PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathyZhiyu Peng0Zhiyu Peng1Zhiyu Peng2Zhiyu Peng3Rui Huang4Rui Huang5Rui Huang6Lu Gan7Lu Gan8Lu Gan9Jinghan Wang10Jinghan Wang11Jinghan Wang12Xiaofeng Li13Xiaofeng Li14Xiaofeng Li15Jie Ding16Jie Ding17Jie Ding18Yinan Han19Yinan Han20Yinan Han21Jihong Wu22Jihong Wu23Jihong Wu24Kang Xue25Kang Xue26Kang Xue27Jie Guo28Jie Guo29Jie Guo30Rui Zhang31Jiang Qian32Ruiqi Ma33Ruiqi Ma34Ruiqi Ma35Department of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaDepartment of Ophthalmology, Fudan Eye & ENT Hospital, Shanghai, ChinaLaboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, ChinaNHC Key Laboratory of Myopia, Fudan University, Shanghai, ChinaObjectivesTransforming 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1537365/fullglycolysisinterleukin-11transforming growth factor β1orbital fibroblastGraves’ orbitopathy |
| spellingShingle | 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 PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy Frontiers in Immunology glycolysis interleukin-11 transforming growth factor β1 orbital fibroblast Graves’ orbitopathy |
| title | PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy |
| title_full | PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy |
| title_fullStr | PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy |
| title_full_unstemmed | PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy |
| title_short | PDK2-enhanced glycolysis aggravates fibrosis via IL11 signaling pathway in Graves’ orbitopathy |
| title_sort | pdk2 enhanced glycolysis aggravates fibrosis via il11 signaling pathway in graves orbitopathy |
| topic | glycolysis interleukin-11 transforming growth factor β1 orbital fibroblast Graves’ orbitopathy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1537365/full |
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