Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression.
Adult
Aged
Animals
DNA-Binding Proteins
/ genetics
Diabetic Foot
/ genetics
Epidermis
/ immunology
Female
Humans
Interleukin-1beta
/ genetics
Male
Membrane Proteins
/ genetics
Mice
Mice, Knockout
Middle Aged
Pore Forming Cytotoxic Proteins
/ genetics
Pyroptosis
/ genetics
Staphylococcal Infections
/ genetics
Staphylococcus aureus
/ immunology
Wound Healing
/ genetics
Dermatology
Diabetes
Inflammation
Molecular pathology
Skin
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 12 2021
15 12 2021
Historique:
received:
23
09
2019
accepted:
27
10
2021
pubmed:
4
11
2021
medline:
7
1
2022
entrez:
3
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34730110
pii: 133727
doi: 10.1172/JCI133727
pmc: PMC8670843
doi:
pii:
Substances chimiques
AIM2 protein, human
0
Aim2 protein, mouse
0
DNA-Binding Proteins
0
IL1B protein, human
0
IL1B protein, mouse
0
Interleukin-1beta
0
MPEG1 protein, human
0
Membrane Proteins
0
Mpeg1 protein, mouse
0
Pore Forming Cytotoxic Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINR NIH HHS
ID : R01 NR015649
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK119085
Pays : United States
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