PERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in sepsis-associated
Guo Xiaofeng1,2, Wu You1, Jia Qi1
1Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, China.
Aims:
Sepsis-associated encephalopathy (SAE) is a common but serious complication in septic survivors and often causes long-term cognitive impairments. The role of RIPK3-participated necroptosis in SAE remains obscured. STING is a key molecule in regulating necroptosis and apoptosis. However, there is uncertainty as to the mechanisms of STING in CLP-induced SAE. The aim of this study was to investigate whether STING is involved in the underlying mechanism of SAE.
Methods:
The contextual fear conditioning test (CFCT) assesses cognitive impairment. A transmission electron microscope (TEM) was used to notice the necroptosis. Western blotting and immunofluorescence labeling were applied for the observation of related proteins.
Results:
The phosphorylated STING in the hippocampal neuron of SAE mice was significantly elevated. Knocking down STING inhibited necroptosis and attenuated cognitive impairment in SAE mice. Moreover, RIPK3-/- mice had less cognitive deficit in the SAE model. However, STING overexpression did not deteriorate cognitive impairment in RIPK3-/- mice with SAE, indicating that STING is upstream involved in necroptosis. Furthermore, PERK inhibition ameliorated cognitive deficits through a STING-dependent pathway in SAE mice.
Conclusion:
PERK-STING-RIPK3 pathway facilitates cognitive impairment by inducing neuronal necroptosis in the pathology of SAE, which provided a new therapeutic target in SAE treatment.
