Scientists discover T cell-related negative regulatory molecular pathway
Researchers from Shanghai Jiaotong University School of Medicine and Cleveland Clinic in the United States have confirmed in new research that Act1 in NG2 + glial cells selectively mediates IL-17-induced experimental autoimmune encephalomyelitis (EAE) onset. The research findings were published online in the September 1 issue of "Nature Neuroscience" (Nature Neuroscience) magazine.
The corresponding author of the paper is Dr. Xiaoxia Li (Transliteration) of Cleveland Clinic in the United States. The experimental design and most of the experimental work and data analysis were completed by the first author, Dr. Zizhen Kang of Shanghai Jiaotong University School of Medicine. Kang Zizhen's main research direction is immunity and disease, focusing on neuroimmunology.
Multiple sclerosis is an inflammatory demyelinating disease of the human central nervous system mediated by T cells, characterized by inflammatory demyelinating accompanied by neurodegenerative, but the exact molecular mechanism is still unclear . Injecting many components of myelin into animals can induce EAE. Studying the EAE model can help determine the immunopathogenic events associated with the formation of inflammatory diseases of the autoimmune central nervous system. In the early stages of EAE, in addition to T cell activation and expansion, there are antigen-presenting cells (APC) producing cytokines that regulate the effect of CD4 + T cell differentiation, including Th1, TNFα, and Th17 T cell lines.
It is worth noting that some recent studies have shown that Th1 cells and Th17 cells can induce EAE through different mechanisms. EAE is significantly inhibited in mice lacking IL-17 or IL-17R, and IL-17-specific inhibition can reduce inflammation, indicating that IL-17-mediated signaling is extremely important during the EAE effect stage. However, it is not clear how IL-17 participates in the formation and pathogenesis of EAE.
Act1 (NF-κB activator 1) is an important intracellular linker protein (adaptor) for IL-17 signaling. In previous studies, the research team reported that removal of mouse neuroectoderm lineage, including neurons, oligodendrocytes, and astrocytes, the key IL-7 receptor signal transducer Act1, can be reduced The severity of the small EAE.
In this new article, the researchers explored the cytological basis of this discovery. They found that removing Act1 in neurons or mature oligodendrocytes did not affect the course of EAE disease, and that removing Act1 in astrocytes only slightly affected the course of disease. Removal of Act1 in NG2 + glial cells will significantly reduce the severity of EAE. Moreover, the researchers confirmed that IL-17 induces the expression of characteristic inflammatory mediators in NG2 + glial cells. IL-17 also strongly inhibited the maturation of oligodendrocyte cell lines in vitro, reducing their survival.
These data confirm that NG2 + glial cells are the main central nervous system cell targets of IL-17 in EAE. The oligodendrocyte cell line is sensitive to IL-17-mediated toxicity, further indicating a direct link between inflammation and neurodegenerative degeneration in multiple sclerosis.
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