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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
VCPIP1 ameliorates sepsis-associated encephalopathy by promoting microglia autophagy via the PI3K/AKT/mTOR pathway
Jing Zuo1, Ruiwen Ding1, Xing Wang1
1The Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Wuchang, 169 Donghu Road, Hubei Province, China.
Abstract:
Sepsis-associated encephalopathy (SAE) is acute diffuse brain dysfunctional clinically caused by systemic infections originating outside the central nervous system (CNS), characterized by acute delirium, coma, and persistent cognitive dysfunction. Multiple studies have demonstrated a crucial role of microglia in the development of SAE. Bioinformatics analysis of the Human Protein Atlas and single-cell RNA sequencing datasets revealed that valosin-containing protein interaction protein 1 (VCPIP1) is expressed at the highest levels in hippocampal microglia, suggesting its potential involvement in neuroinflammatory regulation. In a murine cecal ligation and perforation (CLP) model of SAE, VCPIP1 was upregulated in hippocampal tissue. VCPIP1 deletion could exacerbate learning and memory impairment in CLP-induced conditions, along with suppressed microglial autophagy and increased proinflammatory cytokine production. Mechanistically, VCPIP1 deficiency activated the PI3K/AKT/mTOR signaling axis in microglia, thereby inhibiting autophagic flux. Inhibiting activation of PI3K by LY294002 reversed these effects, restoring autophagy, attenuating neuroinflammation, and mitigating neuronal injury. These results suggest that VCPIP1 improves autophagy by inhibiting the PI3K/AKT/mTOR pathway, highlighting its potential as a therapeutic target for SAE.
Insights
Valosin-containing protein interaction protein 1 (VCPIP1) in microglia regulates brain function during sepsis-associated encephalopathy (SAE). Upregulating VCPIP1 enhances microglial autophagy, reducing neuroinflammation and cognitive deficits in SAE.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Sepsis-associated encephalopathy (SAE) is a severe neurological complication of systemic infections.
- Microglia play a critical role in the pathogenesis of SAE.
- Valosin-containing protein interaction protein 1 (VCPIP1) is highly expressed in microglia and implicated in neuroinflammation.
Purpose of the Study:
- To investigate the role of VCPIP1 in microglia during SAE.
- To elucidate the underlying molecular mechanisms of VCPIP1 in SAE pathogenesis.
- To explore VCPIP1 as a potential therapeutic target for SAE.
Main Methods:
- Bioinformatics analysis of Human Protein Atlas and single-cell RNA sequencing data.
- Establishment of a murine cecal ligation and perforation (CLP) model for SAE.
- Assessment of learning and memory, microglial autophagy, cytokine production, and signaling pathway activation (PI3K/AKT/mTOR) in wild-type and VCPIP1-deficient mice.
- Pharmacological inhibition of PI3K using LY294002.
Main Results:
- VCPIP1 is upregulated in hippocampal microglia in a murine model of SAE.
- VCPIP1 deficiency exacerbates cognitive impairment, suppresses microglial autophagy, and increases pro-inflammatory cytokine production in SAE.
- VCPIP1 deficiency activates the PI3K/AKT/mTOR pathway, inhibiting autophagic flux.
- Inhibition of PI3K with LY294002 restored autophagy, reduced neuroinflammation, and mitigated neuronal injury.
Conclusions:
- VCPIP1 plays a protective role in SAE by promoting microglial autophagy via inhibition of the PI3K/AKT/mTOR pathway.
- VCPIP1 deficiency leads to impaired autophagy and heightened neuroinflammation in SAE.
- VCPIP1 represents a promising therapeutic target for mitigating neuroinflammation and cognitive dysfunction in SAE.
