A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response:: TNF-α is neither necessary nor sufficient
A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response:: TNF-α is neither necessary nor sufficient
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DOI：
10.4049/jimmunol.178.11.7334
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Hooper, D. Craig
中科院分区：
文献类型：
--
作者：
Phares, Timothy W.;Fabis, Marzena J.;Hooper, D. Craig
血脑屏障（BBB）通透性升高与免疫和炎症细胞对中枢神经系统组织的保护性和病理性入侵有关。虽然各种各样的过程都涉及到血脑屏障的变化，导致完整性的丧失，但对于它们的诱导尚未达成共识。tnf - α经常被认为是血脑屏障通透性增加的原因，但越来越多的证据表明，过氧亚硝酸盐（ONOO-）依赖的自由基可能是直接触发因素。我们在这里证明，小鼠血脑屏障通透性的增强，无论是与狂犬病毒（RV）清除还是与中枢神经系统自身免疫有关，在缺乏tnf - α的情况下都没有改变。此外，在没有T细胞的情况下，RV感染诱导中枢神经系统组织中tnf - α a的表达对血脑屏障的完整性没有影响。在中枢神经系统感染时，需要CD4 T细胞增强血脑屏障的通透性，而CD8 T细胞和B细胞则不需要。与中枢神经系统自身免疫一样，RV感染后血脑屏障通透性升高明显是由ONOO-介导的。然而，与入侵细胞产生ONOO相反，ONOO与中枢神经系统炎症的发病机制有关，在病毒清除过程中，ONOO是由ifn - γ刺激的神经血管内皮细胞产生的，没有病理后遗症。
Elevated blood-brain barrier (BBB) permeability is associated with both the protective and pathological invasion of immune and inflammatory cells into CNS tissues. Although a variety of processes have been implicated in the changes at the BBB that result in the loss of integrity, there has been no consensus as to their induction. TNF-alpha has often been proposed to be responsible for increased BBB permeability but there is accumulating evidence that peroxynitrite (ONOO-)-dependent radicals may be the direct trigger. We demonstrate here that enhanced BBB permeability in mice, whether associated with rabies virus (RV) clearance or CNS autoimmunity, is unaltered in the absence of TNF-alpha. Moreover, the induction of TNF-alpha a expression in CNS tissues by RV infection has no impact on BBB integrity in the absence of T cells. CD4 T cells are required to enhance BBB permeability in response to the CNS infection whereas CD8 T cells and B cells are not. Like CNS autoimmunity, elevated BBB permeability in response to RV infection is evidently mediated by ONOO-. However, as opposed to the invading cells producing ONOO- that have been implicated in the pathogenesis of CNS inflammation, during virus clearance ONOO- is produced without pathological sequelae by IFN-gamma-stimulated neurovascular endothelial cells.