Bilirubin impacts microglial autophagy via the Akt-mTOR signaling pathway.
Rats
Animals
Microglia
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Bilirubin
/ pharmacology
Kernicterus
/ metabolism
Inflammasomes
/ metabolism
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Neuroinflammatory Diseases
Signal Transduction
Autophagy
/ physiology
TOR Serine-Threonine Kinases
/ metabolism
Mammals
/ metabolism
autophagy
bilirubin
microglia
neuroinflammation
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
revised:
03
09
2023
received:
11
02
2023
accepted:
26
09
2023
medline:
13
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
Bilirubin encephalopathy is a severe complication of neonatal hyperbilirubinemia. With elevation of serum unconjugated bilirubin (UCB) levels, UCB crosses the blood-brain barrier and possibly leads to neurological dysfunction. Neuroinflammation is recognized as a prominent pathological feature in bilirubin encephalopathy. Recent studies have suggested that autophagy plays a crucial role in the inflammatory response. However, the potential effect of microglial autophagy in the pathogenesis of bilirubin encephalopathy remains uncertain. The in vitro findings verified that in primary cultured microglia, UCB significantly reduced the ratio of LC3B-II to LC3B-I and downregulated the expression of ATG5, Beclin-1, and ATG7, while increasing the expression of p62/SQSTM1. The results showed that UCB could decrease the number of mCherry-EGFP-LC3 positive puncta, even when chloroquine (CQ) was applied to block the microglial autophagy flux. Mechanistically, UCB was found to upregulate the expression of TLR4 and increase the phosphorylation levels of Akt and mammalian target of rapamycin (mTOR). Promoting microglial autophagy by treatment with Rapamycin (RAPA), an mTOR inhibitor, decreased the levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and IL-1β, rescued microglial overactivation, and improved neurological functions. These data indicated that UCB could impact microglial autophagy via the Akt-mTOR signaling pathway and synergistically promote neuroinflammatory responses. Enhancing autophagy might disrupt the assembly of NLRP3 inflammasome, attenuate UCB-induced neuroinflammation, and improve the prognosis of model rats with bilirubin encephalopathy. In conclusion, this study implies that regulating microglial autophagy might be a promising therapeutic strategy for bilirubin encephalopathy.
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Bilirubin
RFM9X3LJ49
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
mTOR protein, rat
EC 2.7.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
582-599Subventions
Organisme : National Natural Science Foundation of China
ID : 81971426
Organisme : Postgraduate Research Innovation Project of Chongqing
ID : CYB22213
Organisme : Postgraduate Research Innovation Project of Chongqing
ID : CYS21227
Organisme : Key Project for Technological Innovation and Application Development of Chongqing
ID : CSTB2022TIAD-KPX0147
Organisme : Science and Technology Research Program of Chongqing Education Commission
ID : KJZD-M202300403
Informations de copyright
© 2023 International Society for Neurochemistry.
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