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ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.
- Source :
-
Cell death & disease [Cell Death Dis] 2024 Jun 11; Vol. 15 (6), pp. 407. Date of Electronic Publication: 2024 Jun 11. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Reactive Oxygen Species metabolism
Mice
Keratinocytes metabolism
Keratinocytes drug effects
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Mitochondria metabolism
Mitochondria drug effects
Wound Healing drug effects
Endoplasmic Reticulum metabolism
Endoplasmic Reticulum drug effects
Inflammasomes metabolism
Interleukin-1beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 15
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 38862500
- Full Text :
- https://doi.org/10.1038/s41419-024-06765-9