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Toxicol Appl Pharmacol ; 485: 116890, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38492674

ABSTRACT

Ricin (ricin toxin, RT) has the potential to cause damage to multiple organs and systems. Currently, there are no existing antidotes, vaccinations, or effective therapies to prevent or treat RT intoxication. Apart from halting protein synthesis, RT also induces oxidative stress, inflammation and autophagy. To explore the mechanisms of RT-induced inflammatory injury and specific targets of prevention and treatment for RT poisoning, we characterized the role of cross-talk between autophagy and NLRP3 inflammasome in RT-induced damage and elucidated the underlying mechanisms. We showed that RT-induced inflammation was attributed to activation of the TLR4/MyD88/NLRP3 signaling and ROS production, evidenced by increased ASC speck formation and attenuated TXNIP/TRX-1 interaction, as well as pre-treatment with MCC950, MyD88 knockdown and NAC significantly reduced IL-1ß, IL-6 and TNF-α mRNA expression. In addition, autophagy is also enhanced in RT-triggered MLE-12 cells. RT elevated the levels of ATG5, p62 and Beclin1 protein, provoked the accumulation of LC3 puncta detected by immunofluorescence staining. Treatment with rapamycin (Rapa) reversed the RT-caused TLR4/MyD88/NLRP3 signaling activation, ASC specks formation as well as the levels of IL-1ß, IL-6 and TNF-α mRNA. In conclusion, RT promoted NLRP3 inflammasome activation and autophgay. Inflammation induced by RT was attenuated by autophagy activation, which suppressed the NLRP3 inflammasome. These findings suggest Rapa as a potential therapeutic drug for the treatment of RT-induced inflammation-related diseases.


Subject(s)
Autophagy , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Ricin , Signal Transduction , Autophagy/drug effects , Animals , Inflammasomes/metabolism , Inflammasomes/drug effects , Ricin/toxicity , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mice , Signal Transduction/drug effects , Inflammation/metabolism , Inflammation/chemically induced , Cell Line , Toll-Like Receptor 4/metabolism , Myeloid Differentiation Factor 88/metabolism , Myeloid Differentiation Factor 88/genetics , Mice, Inbred C57BL , Reactive Oxygen Species/metabolism
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