期刊
JOURNAL OF IMMUNOLOGY
卷 176, 期 5, 页码 3115-3126出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.5.3115
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- NINDS NIH HHS [NS11920, NS40137] Funding Source: Medline
The purinergic receptor P2X(7)R is a nucleotide-gated ion channel that has been proposed to function as a major regulator of inflammation. In this study we examined the role of this receptor in regulating inflammation in the CNS by determining the effects of the loss of this receptor (P2X(7)R(-/-)) on experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We show here that P2X(7)R(-/-) mice developed more severe clinical and pathological expression of EAE than wild type (WT) controls and that spleen and lymph node cells from P2X(7)R(-/-) mice proliferated more vigorously to Ag in vitro. Bone marrow (BM) radiation chimeras revealed that enhanced susceptibility to EAE was detected in chimeric mice of WT host engrafted with P2X(7)R(-/-) BM cells, indicating that the genotype of the BM cells regulated disease susceptibility. Coculture of P2X(7)R(-/-) macrophages with WT lymphocytes and vice versa showed that enhanced proliferative activity resided within the P2X(7)R(-/-) lymphocyte population and correlated with reduced levels of IFN-gamma and NO and apoptosis of lymphocytes. mRNA and protein for IFN-gamma were also significantly reduced in the CNS of P2X(7)R(-/-) mice with EAE. FACS analysis of cells isolated from the CNS showed significantly fewer annexin V/propidium iodide-positive lymphocytes in the CNS of P2X(7)R(-/-) mice early in the disease, and TUNEL staining of inflamed CNS tissues supported this result. From these data we conclude that enhanced susceptibility of P2X(7)R(-/-) mice to EAE reflects a loss of apoptotic activity in lymphocytes, supporting an important role for this receptor in lymphocyte homeostasis.
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