The Preliminary Mechanism Of Cognitive Dysfunction Caused By Gram-negative Bacteria Infection

Objective: Infection is an important global public health challenge.Severely infected patients often develop encephalopathy symptoms such as disturbance of consciousness,which can increase the mortality rate of patients.Some survivors also develop persistent cognitive impairment,which seriously affects their quality of life after discharge from hospital.Therefore,it is very important to explore the mechanism of cognitive impairment caused by infection.Gram-negative bacteria is one of the main pathogenic bacteria of severe infection.Endotoxemia is an internationally recognized animal model of gram-negative bacteria infection.Previous studies have shown that the non-canonical inflammasome pathway of pyroptosis mediated by Caspase-11 plays a key role in the lethality of endotoxemia,but its role and molecular mechanism in cognitive impairment remain unclear.The purpose of this study was to investigate the role and mechanism of the non-canonical inflammasome pathway in the cognitive function of endotoxemia mice.Methods: LPS intraperitoneal injection of endotoxemia mouse model(control group was intraperitoneal injection of normal saline)was established in wild-type(WT),Caspase-11 KO,GSDMD KO,IL-1R KO mice,chimeric mice,and inhibitor intervention mice.(1)New object recognition test and Morris water maze test were used to detect the cognitive function of mice.(2)The changes of microglia in the hippocampus of mice were observed by immunofluorescence method.(3)Serum levels of IL-1α,IL-1β,TNF-α and IL-6 were determined by ELISA.(4)Western Blotting was used to detect the expression of microglia-specific protein Iba1 and astroglia-specific protein GFAP in mouse hippocampus.(5)The changes of blood-brain barrier permeability in mice were detected by Evans blue.Results: In the endotoxemia model:(1)WT mice showed cognitive impairment in the new object recognition and water maze tasks,and the cognitive function of Caspase-11 KO,GSDMD KO and IL-1R KO mice improved to varying degrees,among them,non-hematopoietic Caspase-11 promoted the occurrence of cognitive impairment,and inhibition of Caspase-11 improved the cognitive dysfunction in mice.(2)The activation of microglia in the hippocampus of WT mice was obvious and lasted for a long time,and the activation levels of Caspase-11 KO and GSDMD KO mice were decreased.(3)The expressions of Iba1 and GFAP were upregulated in the hippocampus of WT mice,and the expressions of Caspase-11 KO and GSDMD KO were down-regulated.(4)Serum levels of IL-1α,IL-1β,TNF-α and IL-6 increased in WT mice,but TNF-α and IL-6increased in Caspase-11 KO and GSDMD KO mice with IL-1α and IL-1βdecreased.(5)BBB permeability was increased in WT mice,but not in Caspase-11 KO and GSDMD KO mice.Conclusion: non-canonical inflammasome pathway of pyroptosis mediates cognitive dysfunction in endotoxemia mice by altering bloodbrain barrier permeability and inducing inflammatory effects.