Macrophages are important players in the maintenance of tissue homeostasis¹. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma², 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 individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling 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.

巨噬细胞在维持组织稳态方面发挥着重要作用¹ 。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² ，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 PBM 调节 CSF 流动动力学。我们鉴定了表达高水平 CD163 和 LYVE1（清道夫受体蛋白）的 PBM 亚群，与脑动脉树密切相关，并表明 LYVE1 ⁺ PBM 调节驱动脑脊液流动的动脉运动。 PBM 的药理学或遗传耗竭导致细胞外基质蛋白积累，阻碍脑脊液进入血管周围空间并损害中枢神经系统灌注和清除。脑池内注射巨噬细胞集落刺激因子后，与衰老相关的 PBM 改变和 CSF 动力学损伤得到恢复。从阿尔茨海默病 (AD) 患者和非 AD 个体获得的单核 RNA 测序数据表明，PBM 上的吞噬作用、内吞作用和干扰素-γ 信号传导发生了变化，这些通路在 AD 小鼠模型中得到了证实。总的来说，我们的结果将 PBM 确定为脑脊液流动动力学的新细胞调节剂，可以在药理学上减轻与衰老和 AD 相关的大脑清除缺陷。