ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Mitochondria
/ metabolism
Wound Healing
/ drug effects
Endoplasmic Reticulum
/ metabolism
Humans
Animals
Inflammasomes
/ metabolism
Interleukin-1beta
/ metabolism
Reactive Oxygen Species
/ metabolism
Mice
Keratinocytes
/ metabolism
Mice, Inbred C57BL
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
11 Jun 2024
11 Jun 2024
Historique:
received:
01
02
2024
accepted:
21
05
2024
revised:
14
05
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
11
6
2024
Statut:
epublish
Résumé
Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.
Identifiants
pubmed: 38862500
doi: 10.1038/s41419-024-06765-9
pii: 10.1038/s41419-024-06765-9
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
Inflammasomes
0
Interleukin-1beta
0
Reactive Oxygen Species
0
NLRP3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
407Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG-23670
Informations de copyright
© 2024. The Author(s).
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