Parenchymal Border Macrophages Regulate the Flow Dynamics of the Cerebrospinal Fluid

Overview

Journal Nature

Specialty Science

Date 2022 Nov 9

PMID 36352225

Authors

Antoine Drieu

Siling Du

Steffen E Storck

Justin Rustenhoven

Zachary Papadopoulos

Taitea Dykstra

Fenghe Zhong

Kyungdeok Kim

Susan Blackburn

Tornike Mamuladze

Oscar Harari

Celeste M Karch

Randall J Bateman

Richard Perrin

Martin Farlow

Jasmeer Chhatwal

Song Hu

Gwendalyn J Randolph

Igor Smirnov

Jonathan Kipnis

Affiliations

Soon will be listed here.

Abstract

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 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.

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