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A new cell death program regulated by toll-like receptor 9 through p38 mitogen-activated protein kinase signaling pathway in a neonatal rat model with sepsis associated encephalopathy

查看全文 作　　者：Ruixi [1]Zhou;Junjie [2]Ying;Xia [1,2]Qiu;Luting [1,2]Yu;Yan [1,2]Yue;Qian [1,2]Liu;Jing [1]Shi;Xihong [1,2]Li;Yi [1,2]Qu;Dezhi [2]Mu 高影响力作者 机构地区：[1]Department of Pediatrics,West China Second University Hospital,Sichuan University,Chengdu,Sichuan 610041,China;[2]Key Laboratory of Birth Defects and Related Diseases of Women and Children,Sichuan University,Ministry of Education,Chengdu,Sichuan 610041,China高影响力机构 出　　处：《Chinese Medical Journal》索引2022年第12期,共12页高影响力期刊 基　　金：This work was supported by grants from the National Natural Science Foundation of China(Nos.81630038,81771634,81842011,81801629,81971433,81971428,and 82071353);the National Key Research and Development Program(Nos.2017YFA0104200 and 2017YFA0104201);the grants from the Science and Technology Bureau of Sichuan Province(Nos.2021YJ0017 and 2020YFS0041);the Fundamental Research Funds for the Central University(No.SCU2020D006);the National Key Project of Neonatal Children(No.1311200003303). 摘　　要：Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell death.However,the cell death programs involved and their underlying mechanisms are not clear.This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods:A neonatal rat model of SAE was established by cecal ligation and perforation.Survival rate and vital signs(mean arterial pressure and heart rate)were monitored,nerve reflexes were evaluated,and cortical pathological changes were observed by hematoxylin and eosin staining.The expression of pyroptosis,apoptosis,and necroptosis(PANoptosis)-related proteins,mitogen-activated protein kinase(MAPK),and its upstream regulator toll-like receptor 9(TLR9)were detected.The expression of TLR9 in neurons was observed by immunofluorescence staining.The ultrastructure of neurons was observed by transmission electron microscope.Results:First,PANoptosis was found in cortical nerve cells of the SAE rats.Meanwhile,the subunits of MAPKs,p38 MAPK,Jun N-terminal kinase,and extracellular signal-regulated kinase(ERK)were activated.After pharmacologically inhibiting each of the subunits,only p38 MAPK was found to be associated with PANoptosis.Furthermore,blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis.When necroptosis was pharmacologically inhibited,apoptosis and pyroptosis were reactivated.Finally,we found that the expression of TLR9,a regulator of MAPKs,was significantly increased in this model.After down-regulation of TLR9,p38 MAPK,and ERK signaling pathways were inhibited,which led to the inhibition of PANoptosis.Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats.TLR9 activated PANoptosis through the p38 MAPK signaling pathway.TLR9 may work as a potential target for SAE treatment. 关 键 词：Sepsis associated encephalopathy TLR9 Apoptosis PYROPTOSIS NECROPTOSIS p38 mitogen-activated protein kinase
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