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Research Article| Volume 136, 155293, November 2022

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Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy

  • Author Footnotes
    1 These authors contributed equally.
    Yanjun Wen
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China

    Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

    NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200032, China
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  • Author Footnotes
    1 These authors contributed equally.
    Xin Chen
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

    National Clinical Research Center for Oral Disease, Shanghai, 200011, China

    Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China
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  • Huazhang Feng
    Affiliations
    Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

    Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China
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  • Xu Wang
    Affiliations
    Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

    National Clinical Research Center for Oral Disease, Shanghai, 200011, China

    Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China
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  • Xiaoli Kang
    Affiliations
    Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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  • Peiquan Zhao
    Affiliations
    Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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  • Chen Zhao
    Affiliations
    Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China

    NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200032, China
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  • Yan Wei
    Correspondence
    Corresponding author at: Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China.
    Affiliations
    Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China

    NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200032, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally.

      Highlights

      • Kdm6a is the epigenetic switch in microglia/macrophages and upregulated by high glucose challenge.
      • Loss of Kdm6a in microglia/macrophages ameliorated the retinal thickness decreasing, inflammation, and visual impairment.
      • Lcn2 is regulated by Kdm6a in microglia/macrophages and impact the glycolysis of photoreceptors.
      • Our study provides a valuable strategy to inhibit the progression of diabetic retinopathy by targeting the Kdm6a/Lcn2 axis.

      Abstract

      Diabetic retinopathy (DR) is one of the leading causes of severe visual impairment worldwide. However, the role of adaptive immune inflammation driven by microglia/macrophages in DR is not yet well elucidated. Kdm6a is a histone demethylase that removes the trimethyl groups of histones H3K27 and plays important biological roles in activating target genes. To elucidate the role of Kdm6a in microglia/macrophages in diabetic retinas, we established diabetic animal models with conditional knockout mice to investigate the impacts of Kdm6a deficiency. The RNA-seq analysis, mass spectrum examination, immunohistochemistry and detection of enzyme activities were used to elucidate the effect of Kdm6a deletion on gene transcription in microglia/macrophages. The expression of Kdm6a was increased in the retinas of diabetic mice compared to the control group. Loss of Kdm6a in microglia/macrophages ameliorated the diabetes-induced retinal thickness decrease, inflammation, and visual impairment. Kdm6a in microglia/macrophages regulated Lcn2 expression in a demethylase activity-dependent manner and inhibited glycolysis progression in photoreceptor cells through Lcn2. These results suggest that Kdm6a in microglia/macrophages aggravated diabetic retinopathy by promoting the expression of Lcn2 and impairing glycolysis progression in photoreceptor cells.

      Graphical abstract

      Abbreviations:

      DR (diabetic retinopathy), Kdm6a (Histone lysine demethylase 6a), Lcn2 (Lipocalin-2), H3k27me3 (tri-methyl groups on histone 3 lysine 27), IRBP (interphotoreceptor retinoid-binding protein)

      Keywords

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