| Survivors of severe sepsis are significantly more likely to develop neurodegenerative diseases.Sepsis can cause acute non-infectious inflammation of the central nervous system,if unresolved,may cause chronic neuroinflammation and resultant neurodegenerative diseases.Continuous activation of microglia is a key pathological factor in the transition from acute to chronic neuroinflammation,but its mechanism has not yet been elucidated.Nod-like receptor protein 3（NLRP3）is an intracellular innate immune receptor,and interleukin-1β（IL-1β）is an important cytokine.The purpose of this study is to investigate the role of microglia NLRP3-IL-1βaxis in sepsis neuroinflammation,and to help people better understand the mechanism of chronic neuroinflammation and neurodegeneration after sepsis.This study uses a widely used endotoxemia Lipopolysaccharides（LPS）mouse model.This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson’s disease,thus,providing a unique opportunity for studying phase transition of neuroinflammation and the occurrence of neurodegenerative diseases.C57BL/6J,NLRP3-/-,and IL-1R1-/-mice were employed.Mild and severe endotoxemia were produced by LPS i.p.injection at 1 or 5 mg/kg.Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by q PCR or ELISA and microglial activation by immunohistochemical analysis.Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation andα-synuclein phosphorylation.LPS-elicited initial increases in mouse brain m RNA levels of tumor necrosis factor receptorα（TNFα）,IL-6,IL-1β,and Monocyte Chemoattractant Protein-1（MCP-1）,and nigral microglial activation.In the early stage of sepsis,the increase of brain inflammatory factor m RNA and the level of microglia activation are not significantly related to the dose of LPS injected.On the contrary,the delayed release of mature IL-1βin the brain is related to the dose of LPS,and the continuous activation of microglia in the substantia nigra is only found in the brains of mice in the high-dose LPS treatment group,suggesting that the level of mature IL-1βin the brain tissue is related to the chronicity of neuroinflammation.Further experiments found that LPS-elicited increase in brain mature IL-1βbut not IL-1αlevel was NLRP3-dependent.After high dose LPS treatment,deficiency of NLRP3 or IL-1R1（a functional receptor for IL-1β）did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation.Genetic or pharmacological inhibition of the NLRP3-IL-1βaxis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including major histocompatibility complex II（MHC-II）,NOX2,and Macrophage receptor 1（Mac1）,and protected dopaminergic neurons.Ten months after LPS-elicited severe endotoxemia,nigral persisted microglial activation,elevated nitrosylated proteins and phosphorylatedα-synuclein,and significant neuronal degeneration developed in wild-type mice but not in NLRP3-/-or IL-1R1-/-mice.This study uncovers that the NLRP3-IL-1βsignal axis of microglia does not affect the occurrence of acute neuroinflammation in sepsis,but determines whether the inflammation resolves or changes to low-level persistent chronic neuroinflammation.These findings also provide potential targets for developing therapy for severe systemic sepsis-associated neurodegeneration. |
