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IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wounds

  • Ruchi Roy
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA
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  • Janet Zayas
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA

    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA
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  • Mohamed F. Mohamed
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA
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  • Anahita Aboonabi
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA
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  • Kaylee Delgado
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA
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  • Jennillee Wallace
    Affiliations
    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA
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  • Mohammad Bayat
    Affiliations
    Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Price Institute of Surgical Research, University of Louisville and Noveratech LLC. of Louisville, Louisville, Kentucky, USA
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  • Timothy M. Kuzel
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA
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  • Jochen Reiser
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
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  • Sasha H. Shafikhani
    Correspondence
    Correspondence: Sasha H. Shafikhani, Rush University Medical Center, 1735 W. Harrison Street, Chicago, Illinois 60612, USA.
    Affiliations
    Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

    Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA

    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA

    Cancer Center, Rush University Medical Center, Chicago, Illinois, USA
    Search for articles by this author
Published:September 10, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.428
      Persistent inflammation is a major contributor to healing impairment in diabetic chronic wounds. Paradoxically, diabetic wound environment during the acute phase of healing is completely different because it exhibits a reduced macrophage response owing to inadequate expression of CCL2 proinflammatory cytokine. What causes a reduction in CCL2 expression in diabetic wounds early after injury remains unknown. In this study, we report that in contrast to prolonged exposure to high glucose, which makes monocytes proinflammatory, short-term exposure to high glucose causes a rapid monocyte reprogramming, manifested by increased expression and secretion of IL-10, which in an autocrine/paracrine fashion reduces glucose uptake and transforms monocytes into an anti-inflammatory phenotype by dampening signaling through toll-like receptors. We show that IL-10 expression is significantly increased in diabetic wounds during the acute phase of healing, causing significant reductions in toll-like receptor signaling and proinflammatory cytokine production, delaying macrophage and leukocyte responses, and underlying healing impairment in diabetic wounds. Importantly, blocking IL-10 signaling during the acute phase of healing improves toll-like receptor signaling, increases proinflammatory cytokine production, enhances macrophage and leukocyte responses, and stimulates healing in diabetic wounds. We posit that anti–IL-10 strategies have therapeutic potential if added topically after surgical debridement, which resets chronic wounds into acute fresh wounds.

      Abbreviations:

      DFU (diabetic foot ulcer), HG (high glucose), hPBMC (human PBMC), BMDM (bone marrow‒derived monocyte), TLR (toll-like receptor)
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