实验性自身免疫性脑脊髓炎
髓鞘少突胶质细胞糖蛋白
细胞生物学
生物
RAR相关孤儿受体γ
白细胞介素17
炎症
免疫学
髓鞘
中枢神经系统
免疫系统
神经科学
FOXP3型
作者
Sandip Ashok Sonar,Heikrujam Thoihen Meitei,Surojit Karmakar,Amrita Mishra,Shrirang Inamdar,Nibedita Lenka,Girdhari Lal
标识
DOI:10.1016/j.clim.2024.109898
摘要
Myelin antigen-reactive Th1 and Th17 cells are critical drivers of central nervous system (CNS) autoimmune inflammation. Transcription factors T-bet and RORγt play a crucial role in the differentiation and function of Th1 and Th17 cells, and impart them a pathogenic role in CNS autoimmune inflammation. Mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). While T-bet and RORγt are known to regulate the expression of several cell adhesion and migratory molecules in T cells, their role in supporting Th1 and Th17 trafficking to the CNS is not completely understood. More importantly, once Th1 and Th17 cells reach the CNS, how the function of these transcription factors modulates the local inflammatory response during EAE is unclear. In the present study, we showed that myelin oligodendrocyte glycoprotein 35–55 peptide (MOG35–55)-specific Th1 cells deficient in RORγt could cross the blood-brain barrier (BBB) but failed to induce demyelination, apoptosis of neurons, and EAE. Pathogenic Th17 cell-derived cytokines GM-CSF, TNF-α, IL-17A, and IL-21 significantly increased the surface expression of IL-23R on neuronal cells. Furthermore, we showed that, in EAE, neurons in the brain and spinal cord express IL-23R. IL-23-IL-23R signaling in neuronal cells caused phosphorylation of STAT3 (Ser727 and Tyr705) and induced cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1) molecules in an IL-23R-dependent manner and caused apoptosis. Thus, we provided a mechanism showing that T-bet is required to recruit pathogenic Th17 cells to the CNS and RORγt-mediated inflammatory response to drive the apoptosis of IL-23R+ neurons in the CNS and cause EAE. Understanding detailed molecular mechanisms will help to design better strategies to control neuroinflammation and autoimmunity. IL-23-IL-23R signaling promotes apoptosis of CNS neurons.
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