Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage.
Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage.
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DOI：
10.1084/jem.20221929
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发表时间：
2023-07-03
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--
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脑废物的淋巴排水受损发生在衰老和疾病中，但原因仍然难以捉摸。在这里，Rustenhoven等人描述了脑膜免疫细胞衍生的IFNγ如何成为这种与年龄相关的缺陷的基础，并证明了其治疗操作可以改善废物清除。脑膜淋巴网络能够引流脑脊液（CSF）并促进中枢神经系统（CNS）废物的清除。在衰老和阿尔茨海默病中，受损的脑膜淋巴引流促进了中枢神经系统中有毒错误折叠蛋白的积累。逆转这种与年龄相关的功能障碍是增强中枢神经系统废物清除的一种有希望的策略；然而，这种下降背后的机制仍然难以捉摸。在这里，我们证明了年龄相关的脑膜免疫改变是淋巴损伤的基础。老年小鼠脑膜淋巴内皮细胞的单细胞RNA测序揭示了它们对IFNγ的反应，由于T细胞的积累，IFNγ在老年脑膜中增加。通过aav介导的过表达，年轻小鼠脑膜IFNγ的慢性升高可减弱脑脊液排水-与老年小鼠观察到的缺陷相当。在治疗上，ifn - γ中和减轻了与年龄相关的脑膜淋巴功能损伤。这些数据表明，操纵脑膜免疫是一种可行的方法，可以使脑脊液引流正常化，减轻与废物清除受损相关的神经功能障碍。
Impaired lymphatic drainage of brain waste occurs in aging and disease, but the cause remains elusive. Here, Rustenhoven et al. describe how meningeal immune cell–derived IFNγ underlies this age-related deficit and demonstrate its therapeutic manipulation to improve waste clearance. The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV-mediated overexpression attenuated CSF drainage—comparable to the deficits observed in aged mice. Therapeutically, IFNγ neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal.
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影响因子：
64.8
作者：
Filiano AJ;Xu Y;Tustison NJ;Marsh RL;Baker W;Smirnov I;Overall CC;Gadani SP;Turner SD;Weng Z;Peerzade SN;Chen H;Lee KS;Scott MM;Beenhakker MP;Litvak V;Kipnis J
通讯作者：
Kipnis J
影响因子：
30.5
作者：
Alves de Lima K;Rustenhoven J;Da Mesquita S;Wall M;Salvador AF;Smirnov I;Martelossi Cebinelli G;Mamuladze T;Baker W;Papadopoulos Z;Lopes MB;Cao WS;Xie XS;Herz J;Kipnis J
通讯作者：
Kipnis J
影响因子：
7.7
作者：
Absinta M;Ha SK;Nair G;Sati P;Luciano NJ;Palisoc M;Louveau A;Zaghloul KA;Pittaluga S;Kipnis J;Reich DS
通讯作者：
Reich DS
影响因子：
64.8
作者：
Ahn, Ji Hoon;Cho, Hyunsoo;Koh, Gou Young
通讯作者：
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影响因子：
32.4
作者：
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Koh, Gou Young