Severe disease, unaltered leukocyte migration, and reduced IFN-γ production in CXCR3-/- mice with experimental autoimmune encephalomyelitis
Severe disease, unaltered leukocyte migration, and reduced IFN-γ production in CXCR3-/- mice with experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.176.7.4399
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Ransohoff, Richard M.
中科院分区：
文献类型：
--
作者：
Liu, LiPing;Huang, DeRen;Ransohoff, Richard M.
实验性自身免疫性脑脊髓炎（EAE）是一种CD 4（+）Th 1 T细胞介导的CNS疾病，用于研究多发性硬化症的某些方面。CXCR 3是CXCL 10、CXCL 9和CXCL 11的受体，优先在活化的Th 1 T细胞上表达，并已被提出在多发性硬化和EAE期间控制淋巴细胞向发炎CNS的迁移。出乎意料的是，CXCL 10缺陷小鼠对EAE易感，这使得CXCR 3及其配体在这种疾病模型中的作用不确定。在这项研究中，我们报告说，CXCR 3（-/-）小鼠表现出夸大的EAE的严重程度相比，野生型（CXCR 3（+/+））同窝小鼠。令人惊讶的是，在患有EAE的CXCR 3（+/+）和CXCR 3（-/-）小鼠之间，CNS浸润性白细胞既没有定量差异也没有定性差异。与CXCR 3（+/+）小鼠相比，尽管这些炎症浸润相当，但CXCR 3（-/-）EAE小鼠的CNS组织显示血脑屏障破坏加重，炎症脊髓内血管性血友病因子免疫反应性血管更多。患有EAE的CXCR 3（-/-）小鼠的脊髓表现出IFN-γ水平降低，与诱导型NO合酶免疫反应性降低相关，并且来自用MOG（35-55）致敏的CXCR 3（-/-）小鼠的淋巴结T细胞在Ag驱动的回忆应答中比来自CXCR 3（+/+）动物的细胞分泌更少的IFN-γ。CXCR 3（-/-）淋巴结T细胞也显示出增强的Ag驱动的增殖，其通过添加IFN-γ而降低。与先前的研究结果相比，我们的数据显示CXCL 10是EAE中CXCR 3最相关的配体。CXCR 3不控制EAE中的白细胞运输，但调节T细胞IFN-γ的产生和影响疾病严重程度的下游事件。
Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-deficient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3(-/-) mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3(+/+)) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3(+/+) and CXCR3(-/-) mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3(-/-) mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3(+/+) mice. Spinal cords of CXCR3(-/-) mice with EAE demonstrated decreased levels of IFN-gamma, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3(-/-) mice primed with MOG(35-55) secreted less IFN-gamma in Ag-driven recall responses than cells from CXCR3(+/+) animals. CXCR3(-/-) lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-gamma. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-gamma production and downstream events that affect disease severity.