NLRP3/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy

• Published in: Inflammation Vol. 42; no. 1; pp. 306 - 318
• Main Authors: Fu, Qun, Wu, Jing, Zhou, Xiao-Yan, Ji, Mu-Huo, Mao, Qing-Hong, Li, Qing, Zong, Man-Man, Zhou, Zhi-Qiang, Yang, Jian-Jun
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2019; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Caspase; Caspase-1; Cecum; Cognitive ability; Cytokines; Encephalopathy; Hippocampus; Immunology; Inflammation; Internal Medicine; Memory; Neurodegenerative diseases; Original; Original Article; Pathology; Pharmacology/Toxicology; Pyroptosis; Rheumatology; Rodents; Sepsis; pyroptosis; NLRP3; cognitive impairment; pro-inflammatory cytokine; caspase-1
• ISSN: 0360-3997; 1573-2576; 1573-2576
• DOI: 10.1007/s10753-018-0894-4

Sepsis-associated encephalopathy (SAE) is a common complication that leads to long-term cognitive impairments and increased mortality in sepsis survivors. The mechanisms underlying this complication remain unclear and an effective intervention is lacking. Accumulating evidence suggests the nucleotide-binding domain-like receptor protein3 (NLRP3)/caspase-1 pathway is involved in several neurodegenerative diseases. Thus, we hypothesized that the NLRP3/caspase-1 pathway is involved in NLRP3-mediated pyroptosis, maturation and release of inflammatory cytokines, and cognitive deficits in SAE. We used the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Ac-YVAD-CMK to study the role of the NLRP3/caspase-1 pathway in pyroptosis and cognitive deficits in a mouse model of SAE. Mice were randomly assigned to one of six groups: sham+saline, sham+MCC950, sham+Ac-YVAD-CMK, cecal ligation and puncture (CLP)+saline, CLP+MCC950, and CLP+Ac-YVAD-CMK. Surviving mice underwent behavioral tests or had hippocampal tissues collected for histochemical analysis and biochemical assays. Our results show that CLP-induced hippocampus-dependent memory deficits are accompanied by increased NLRP3 and caspase-1 positive cells, and augmented protein levels of NLRP3, caspase-1, gasdermin-D, and pro-inflammatory cytokines in the hippocampus. In addition, administration of MCC950 or Ac-YVAD-CMK rescues cognitive deficits and ameliorates increased hippocampal NLRP3-mediated neuronal pyroptosis and pro-inflammatory cytokines. Our results suggest that the NLRP3/caspase-1 pathway-induced pyroptosis mediates cognitive deficits in a mouse model of SAE.