Mechanism Of IL-33/ST2 In Central Nervous System Diseases

Part ? IL-33/ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulationBackground:Interleukin-33(IL-33)is increasingly being recognized as a key immunomodulatory cytokine in many neurological diseases,but the detailed role of IL-33 in the central nervous system disease is controvisal.Methods:In the present study,wild-type(WT)and IL-33-/-mice received intracerebroventricular(i.c.v.)injection of lipopolysaccharide(LPS)to induce neuroinflammation.Intravital microscopy was employed to examine leukocyte-endothelial interactions in the brain vasculature.The degree of neutrophil infiltration was determined by myeloperoxidase(MPO)staining.Real-time PCR and western blotting were used to detect endothelial activation.Enzyme-linked immunosorbent assay and quantitative PCR were conducted to detect pro-inflammatory cytokine levels in the brain.In vitro,we stimulated brain endothelial cell with IL-33,Western blot were used to detected endothelial activation;we extracted brain primary microglia cells,stimulated with IL-33 or LPS+IL-33,ELISA were used to detected the pro-inflammation in the cell supernant.Results:In IL-33-/-mice,neutrophil infiltration in the brain cortex and leukocyte-endothelial cell interactions in the cerebral microvessels were significantly decreased as compared to WT mice after LPS injection.In addition,IL-33-/-mice showed reduced activation of microglia and cerebral endothelial cells.In vitro results indicated that IL-33 directly activated cerebral endothelial cells and promoted pro-inflammatory cytokine production in LPS-stimulated microglia.Conclusions:Our study indicated that IL-33/ST2 signaling plays an important role in the activation of microglia and cerebral endothelial cells and therefore,is essential in leukocyte recruitment in brain inflammation.Part ? The Role and Mechanism of IL-33/ST2 in MPTP-induced Parkinson ModelBackground:Neuroinflammation activation is associated with neurodegenerative diseases,IL33/ST2 signal plays an important role in the regulation of neuroinflammation,however,its role and mechanism in Parkinson's disease have not been elucidated.Methods:In the present study,wild-type(WT)and IL-33-/-mice received intraperitoneal injection(i.p.)of MPTP to induce Parkinson's model.Immunofluorescence were used to detect cell location of IL-33 and ST2 in the disease status.Besides,immunofluorescence and immunohistochemistry were conducted to detect the dopamine neurons apoptosis and glial activation in the substantia nigra pars compacta of mice.Results:In the Parkinson' s model of WT mice,the expression of IL-33 in midbrain was significantly elevated,but the receptor ST2 was not changed.In the brain,IL-33 is mainly expressed in astrocyte while ST2 is mainly expressed in astrocytes and microglia.Compare to WT mice,immunohistochemical results indicated that in IL-33/-mice,dopamine neurons apoptosis was also significantly increased in the substantia nigra region.In addition,the activation of glial cells in the substantia nigra was significantly increased in IL-33-/-mice.Conclusions:Our preliminary study reveals that IL-33/ST2 signaling affects neuronal apoptosis by regulating the activation of glial cell.