MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis.
MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis.
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DOI：
10.1042/an20130033
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发表时间：
2013-11-26
期刊：
影响因子：
4.7
通讯作者：
Stohlman SA
中科院分区：
文献类型：
--
作者：
Savarin C;Bergmann CC;Hinton DR;Stohlman SA
亚致死性嗜神经冠状病毒 (JHMV) 感染 CNS（中枢神经系统）会引起剧烈的炎症反应。 CD4+ 和 CD8+ T 细胞对于控制感染性病毒至关重要，但代价是组织损伤。了解 T 细胞亚群在发病机制中的贡献的一个谜团在于它们跨 BBB（血脑屏障）的独特迁移模式。 CD4+ T 细胞在血管周围空间短暂积聚，而 CD8+ T 细胞直接迁移到中枢神经系统实质中。由于 MMP（基质金属蛋白酶）促进跨越神经胶质细胞界限的迁移，血管周围袖带中存在的 CD4+ T 细胞对 TIMP（MMP 组织抑制剂）-1 的特异性表达表明 TIMP-1 负责阻止 CD4+ T 细胞迁移到 CNS 实质。使用 TIMP-1 缺陷小鼠，目前的数据表明，在 JHMV 感染期间，血管周围空间内 CD4+ T 细胞的积累增加而不是减少。尽管病毒控制不受血管周围 CD4+ T 细胞滞留的影响，但疾病严重程度降低，并且与 IFNγ（干扰素 γ）产生减少相关。此外，TIMP-1缺陷小鼠中枢神经系统实质中CD4+ T细胞募集的减少与T细胞募集趋化因子或MMP表达受损无关，并且没有发现其他TIMP分子的补偿。这些数据表明，在急性 JHMV 脑炎期间，TIMP-1 在调节 CD4+ T 细胞进入 CNS 实质中具有独立于 MMP 的作用。
Infection of the CNS (central nervous system) with a sublethal neurotropic coronavirus (JHMV) induces a vigorous inflammatory response. CD4+ and CD8+ T cells are essential to control infectious virus but at the cost of tissue damage. An enigma in understanding the contribution of T cell subsets in pathogenesis resides in their distinct migration pattern across the BBB (blood brain barrier). CD4+ T cells transiently accumulate within the perivascular space, whereas CD8+ T cells migrate directly into the CNS parenchyma. As MMPs (matrix metalloproteinases) facilitate migration across the glia limitans, specific expression of the TIMP (tissue inhibitor of MMPs)-1 by CD4+ T cells present in the perivascular cuffs suggested that TIMP-1 is responsible for stalling CD4+ T cell migration into the CNS parenchyma. Using TIMP-1 deficient mice, the present data demonstrate an increase rather than a decrease in CD4+ T cell accumulation within the perivascular space during JHMV infection. Whereas virus control was not affected by perivascular retention of CD4+ T cells, disease severity was decreased and associated with reduced IFNγ (interferon γ) production. Moreover, decreased CD4+ T cell recruitment into the CNS parenchyma of TIMP-1 deficient mice was not associated with impaired T cell recruiting chemokines or MMP expression, and no compensation by other TIMP molecules was identified. These data suggest an MMP-independent role of TIMP-1 in regulating CD4+ T cell access into the CNS parenchyma during acute JHMV encephalitis.