Exosomes Mediate Hippocampal and Cortical Neuronal Injury Induced by Hepatic Ischemia-Reperfusion Injury through Activating Pyroptosis in Rats

Abstract

Background The neuronal injury and cognitive dysfunction after liver transplantation have severe effects on the prognosis and life quality of patients. Accumulating evidence suggests that both exosomes and pyroptosis could participate in hepatic ischemia-reperfusion injury (HIRI) and play key roles in neuronal death. However, the link between exosomes and neuronal pyroptosis in HIRI awaits further investigation. Methods After establishing the HIRI rat models, we primarily studied the role of pyroptosis in hippocampal and cortical neuron injury through detecting NOD-like receptor protein 3 (NLRP3), pro-caspase-1, cleaved-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), gasdermin D (GSDMD), interleukin-1beta (IL-1β), and interleukin-18 (IL-18) expressions with western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Then, we intravenously injected normal male rats with exosomes isolated from the sera of HIRI-challenged rats and pretreated rats with MCC950, a specific inhibitor of NLRP3, and carried out the same assay. We also detected the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in the hippocampal and cortical tissues. Results The results indicated that NLRP3 inflammasome and caspase-1-dependent pyroptosis were activated in the hippocampus and cortex of HIRI rats. Furthermore, serum-derived exosomes from HIRI-challenged rats not only had the ability to cross the blood-brain barrier (BBB) but also had the similar effects on neuronal pyroptosis. Moreover, ROS and MDA productions were induced in the HIRI and exosome-challenged groups. In addition, to some degree, MCC950 could alleviate HIRI-mediated hippocampal and cortical neuronal pyroptosis. Conclusion This study experimentally demonstrated that circulating exosomes play a critical role in HIRI-mediated hippocampal and cortical injury through regulating neuronal pyroptosis.

Hypoxia-preconditioned olfactory mucosa mesenchymal stem cells abolish cerebral ischemia/reperfusion-induced pyroptosis and apoptotic death of microglial cells by activating HIF-1α

“…indicate that cerebral ischemia/reperfusion is involved in the canonical non-infectious pathway of pyroptosis in multiple cell types, including vascular endothelial cells, neurons, and astrocytes involves the canonical noninfectious pathway of pyroptosis [31][32][33]. However, to date, it is not known whether co-culturing OM-MSCs with microglia has a protective effect against either pyroptotic or apoptotic cell death during cerebral I/R injury.…”

Systematic analysis on multiple Gene Expression Omnibus data sets reveals fierce immune response in hepatitis B virus‐related acute liver failure

“…The top 10 GS genes in the key module, namely GUSBP11, KRT23, PLA2G7, IGLL3P, IGLJ3, S100A11, OSBPL3, CMTM7, IL18, CD3D, were selected as the hub genes, which were further confirmed significantly up‐regulation in an independent data set. It was previously reported that KRT23, 37 S100A11 38 and IL18 39 contributed to liver injury. Besides, the serum levels of these three proteins could be detected easily.…”

Baicalein Attenuates Pyroptosis and Endoplasmic Reticulum Stress Following Spinal Cord Ischemia-Reperfusion Injury via Autophagy Enhancement

“…Pyroptosis, a specific pro-inflammatory programmed cell death, is characterized by the swelling and rupture of cells and the lysis and release of pro-inflammatory molecules ( Xing et al., 2020 ; Zheng and Li, 2020 ). Pyroptosis is considered an important factor in models of renal, hepatic and myocardial ischemia and reperfusion injury ( Wu et al., 2016 ; Qiu et al., 2017 ; Zhang et al., 2019 ). Consequently, we speculated that BA may downregulate pyroptosis in SCIRI.…”

“…Pyroptosis is a programmed inflammatory necrotizing cell death mediated by gasdermin D (GSDMD) ( Shi et al., 2017 ). Its main characteristic is the activation of the inflammasome, represented by NLRP3, which can recruit and activate the proteolytic enzyme caspase-1 leading to the cleavage of the pore-forming protein GSDMD and the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and IL18 ( Zhang et al., 2019 ). Studies have indicated that the production of reactive oxygen species (ROS) can activate the NLRP3 inflammasome ( Qiu et al., 2019 ).…”