Back to Search
Start Over
Scutellarin inhibits inflammatory PANoptosis by diminishing mitochondrial ROS generation and blocking PANoptosome formation.
- Source :
-
International immunopharmacology [Int Immunopharmacol] 2024 Sep 30; Vol. 139, pp. 112710. Date of Electronic Publication: 2024 Jul 18. - Publication Year :
- 2024
-
Abstract
- PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-β-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Animals
Mice
Cell Line
Macrophages drug effects
Macrophages metabolism
Macrophages immunology
Anti-Inflammatory Agents pharmacology
Anti-Inflammatory Agents therapeutic use
Necroptosis drug effects
Male
MAP Kinase Kinase Kinases metabolism
Inflammation drug therapy
Signal Transduction drug effects
Zearalenone administration & dosage
Lactones
Resorcinols
Apigenin pharmacology
Apigenin therapeutic use
Glucuronates pharmacology
Glucuronates therapeutic use
Reactive Oxygen Species metabolism
Mitochondria drug effects
Mitochondria metabolism
Mice, Inbred C57BL
Lipopolysaccharides
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 139
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 39029229
- Full Text :
- https://doi.org/10.1016/j.intimp.2024.112710