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PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4

  • Author Footnotes
    7 These authors contributed equally to this work.
    Le Kuai
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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  • Author Footnotes
    7 These authors contributed equally to this work.
    Yan-wei Xiang
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Author Footnotes
    7 These authors contributed equally to this work.
    Qi-long Chen
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Author Footnotes
    7 These authors contributed equally to this work.
    Yi Ru
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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  • Shuang-yi Yin
    Affiliations
    Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China
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  • Wei Li
    Affiliations
    Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China
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  • Jing-si Jiang
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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  • Ying Luo
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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  • Jian-kun Song
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Bing Lu
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Yue Luo
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Bin Li
    Correspondence
    Correspondence: Bin Li, Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of TCM, 110 Ganhe Road, Shanghai 200437, China; Institute of Dermatology, Shanghai Academy of TCM, 110 Ganhe Road, Shanghai 200437, China; Shanghai Skin Disease Hospital of Tongji University, Baode Road 1278, Jing'an District, Shanghai 200443, China.
    Affiliations
    Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    7 These authors contributed equally to this work.
      Persistent chronic inflammation and delayed epithelialization lead to stalled healing in diabetic ulcers (DUs). PD-L1 shows anti-inflammatory and proliferative activities in healing defects, whereas its function in DU pathogenesis remains unknown. Lower levels of PD-L1 were found in DU tissues, and exogenous PD-L1 has therapeutic effects in the healing process by accelerating re-epithelialization and attenuating prolonged inflammation, which contributed to the delayed wound closure. We detected the downstream effectors of PD-L1 using transcriptional profiles and screened the interacting proteins using immunoprecipitation in combination with mass spectrometry and coimmunoprecipitation assays. The biological functions of eIF3I‒PD-L1‒IRS4 axis were tested both in vivo and in vitro. Finally, we validated the expression levels of eIF3I, PD-L1, and IRS4 in DU tissues from human clinical samples by immunohistochemistry staining. Mechanistically, PD-L1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4. These findings identify that the eIF3I‒PD-L1‒IRS4 axis contributes to wound healing defects, which can serve as a potential therapeutic target in DUs.

      Graphical abstract

      Abbreviations:

      DE (differentially expressed), DU (diabetic ulcer), KC (keratinocyte), rb-bFGF (recombinant bovine basic fibroblast growth factor), siRNA (small interfering RNA)
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