2. Academic Validation
  3. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes

Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes

  • Nature. 2022 Jun;606(7915):776-784. doi: 10.1038/s41586-022-04754-6.
Sophia Maschalidi 1 2,  Parul Mehrotra  # 3 4,  Burcu N Keçeli  # 3 4,  Hannah K L De Cleene 3 4,  Kim Lecomte 4 5,  Renée Van der Cruyssen 4 6,  Pauline Janssen 7,  Jonathan Pinney 8 9,  Geert van Loo 4 5,  Dirk Elewaut 4 6,  Ann Massie 7,  Esther Hoste 4 5,  Kodi S Ravichandran 10 11 12 13 14
Affiliations

Affiliations

  • 1 Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium. [email protected].
  • 2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. [email protected].
  • 3 Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.
  • 4 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 5 Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium.
  • 6 Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
  • 7 Laboratory of Neuro-Aging and Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
  • 8 The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
  • 9 Department of Microbiology, Immunology, and Cancer Biology, and the Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
  • 10 Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium. [email protected].
  • 11 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. [email protected].
  • 12 The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 13 Department of Microbiology, Immunology, and Cancer Biology, and the Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 14 Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA. [email protected].
  • # Contributed equally.
PMID: 35614212 DOI: 10.1038/s41586-022-04754-6
Abstract

Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair1-3. Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derived from glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes.

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