研究重磅突破：实质边界巨噬细胞（PBM）驱动脑脊液的流动进而维持脑脊液的清除功能

中文摘要

巨噬细胞是维持组织稳态的重要角色。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，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，研究人员将这些细胞统称为实质边界巨噬细胞（PBM）。在这里，他们证明PBM调节脑脊液流动动力学。他们确定了表达高水平CD163和LYVE1（清道夫受体蛋白）的PBMs亚群，与脑动脉树密切相关，并表明LYVE1+PBMs调节驱动脑脊液流动的动脉运动。PBMs的药理学或遗传耗竭导致细胞外基质蛋白的积累，阻碍CSF进入血管周围空间，损害CNS灌注和清除。脑室内注射巨噬细胞集落刺激因子后，PBMs的老化相关改变和CSF动力学受损得以恢复。从阿尔茨海默病（AD）患者和非AD患者获得的单核RNA测序数据表明，PBMs上的吞噬作用、内吞作用和干扰素-γ信号的变化，这些途径在AD小鼠模型中得到证实，其可作为药物靶向以缓解与衰老和AD相关的脑清除缺陷。

英文摘要

Macrophages are important players in the maintenance of tissue homeostasis. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma, and their role in CNS physiology has not been sufficiently well studied. 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 that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with 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 and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer's disease (AD) and from non-AD inpiduals point to changes in phagocytosis, endocytosis and interferon-γ signaling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.