Regulation of learning and memory by meningeal immunity: a key role for IL-4.
Regulation of learning and memory by meningeal immunity: a key role for IL-4.
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脑膜免疫调节学习和记忆：IL-4 的关键作用。
DOI：
10.1084/jem.20091419
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发表时间：
2010-05-10
影响因子：
15.3
通讯作者：
Kipnis, Jonathan
中科院分区：
文献类型：
--
作者：
Derecki, Noel C.;Cardani, Amber N.;Yang, Chun Hui;Quinnies, Kayla M.;Crihfield, Anastasia;Lynch, Kevin R.;Kipnis, Jonathan
促炎细胞因子已被证明会损害认知;因此，中枢神经系统中的免疫活动被认为对认知功能有害。然而，出乎意料的是，T细胞最近被证明支持学习和记忆，尽管其潜在机制尚不清楚。我们表明，在级联的T细胞为基础的学习和记忆的支持步骤之一发生在脑膜空间。认知任务的执行导致脑膜中产生IL-4的T细胞的积累。脑膜间隙T细胞的耗竭使脑膜髓样细胞倾向于促炎表型。T细胞来源的IL-4至关重要，因为IL-4−/−小鼠表现出偏斜的促炎性脑膜髓样细胞表型和认知缺陷。将IL-4−/−骨髓移植到受辐射的野生型受体中也会导致认知障碍和促炎性偏斜。此外，将野生型T细胞过继转移到IL-4−/−小鼠中可以逆转认知障碍，并减弱脑膜髓样细胞的促炎特征。我们的研究结果表明，T细胞源性IL-4通过脑膜髓样细胞表型和脑源性神经营养因子表达在调节认知功能中起关键作用。这些发现可能会导致开发新的基于免疫的疗法，用于与免疫下降相关的认知障碍。
Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell–based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4–producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell–derived IL-4 was critical, as IL-4−/− mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4−/− bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4−/− mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell–derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline.
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