Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid.
Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid.
复制标题
DOI：
10.1038/s41586-022-05397-3
复制
发表时间：
2022-11
期刊：
影响因子：
64.8
通讯作者：
Kipnis, Jonathan
中科院分区：
文献类型：
--
作者：
Drieu, Antoine;Du, Siling;Storck, Steffen E.;Rustenhoven, Justin;Papadopoulos, Zachary;Dykstra, Taitea;Zhong, Fenghe;Kim, Kyungdeok;Blackburn, Susan;Mamuladze, Tornike;Harari, Oscar;Karch, Celeste M.;Bateman, Randall J.;Perrin, Richard;Farlow, Martin;Chhatwal, Jasmeer;Hu, Song;Randolph, Gwendalyn J.;Smirnov, Igor;Kipnis, Jonathan
巨噬细胞是维持组织稳态的重要参与者。血管周围和软脑膜巨噬细胞位于中枢神经系统（CNS）实质附近，迄今为止，它们在CNS生理学中的作用尚未得到充分研究。鉴于它们与脑脊液（CSF）的持续相互作用和战略定位，我们将这些细胞统称为实质边界巨噬细胞（PBM）。在这里，我们证明PBMs调节CSF流动动力学。我们确定了一个PBMs亚群表达高水平的CD 163和Lyve 1（清道夫受体蛋白），位于靠近脑动脉树，并表明Lyve 1 + PBMs调节动脉运动，驱动CSF流量。PBM的药理学或遗传消耗导致细胞外基质蛋白的积累，阻碍CSF进入血管周围空间，从而损害CNS灌注和清除。在脑池内注射巨噬细胞集落刺激生长因子（M-CSF）后，PBMs的衰老相关改变和CSF动力学受损得到恢复。从阿尔茨海默病（AD）患者和健康对照中获得的人类单核RNA测序数据表明PBM上的吞噬/内吞作用和干扰素-γ（IFNγ）信号传导的变化，这些通路在小鼠AD模型中得到证实。总的来说，我们的研究结果确定PBM作为CSF流动动力学的新型细胞调节剂，这可能是有针对性的，以减轻与衰老和AD相关的脑清除率不足。
Macrophages are important players for the maintenance of tissue homeostasis. Perivascular and leptomeningeal macrophages reside in close proximity to the central nervous system (CNS) parenchyma, and their role in CNS physiology has not been well enough studied to date. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here, we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs expressing high levels of CD163 and Lyve1 (scavenger receptor proteins), located in close proximity to the brain arterial tree, and show that Lyve1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces hence impairing CNS perfusion and clearance. Aging-associated alterations in PBMs and impairment of CSF dynamics were restored upon intracisternal injection of macrophage colony-stimulating growth factor (M-CSF). Human single-nuclei RNA sequencing data obtained from Alzheimer’s disease (AD) patients and healthy controls point to changes in phagocytosis/endocytosis and interferon-gamma (IFNγ) signaling on PBMs, pathways that are corroborated in a mouse AD model. Collectively, our results identify PBMs as novel cellular regulators of CSF flow dynamics, which could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and AD.
登录
查看更多内容
DOI：
10.1007/s00109-017-1573-x
发表时间：
2017-11
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Faraco G;Park L;Anrather J;Iadecola C
通讯作者：
Iadecola C
影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
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：
64.8
作者：
Ahn, Ji Hoon;Cho, Hyunsoo;Koh, Gou Young
通讯作者：
Koh, Gou Young