Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression

J Clin Invest. 2021 Dec 15;131(24):e133727. doi: 10.1172/JCI133727.


Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

Keywords: Dermatology; Diabetes; Inflammation; Molecular pathology; Skin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • Diabetic Foot / genetics
  • Diabetic Foot / immunology*
  • Diabetic Foot / microbiology
  • Epidermis / immunology*
  • Epidermis / microbiology
  • Female
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Pore Forming Cytotoxic Proteins / genetics
  • Pore Forming Cytotoxic Proteins / immunology*
  • Pyroptosis / genetics
  • Pyroptosis / immunology*
  • Staphylococcal Infections / genetics
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / immunology*
  • Wound Healing / genetics
  • Wound Healing / immunology*


  • AIM2 protein, human
  • Aim2 protein, mouse
  • DNA-Binding Proteins
  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin-1beta
  • MPEG1 protein, human
  • Membrane Proteins
  • Mpeg1 protein, mouse
  • Pore Forming Cytotoxic Proteins