Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

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 and Jonathan Kipnis ()
Additional contact information
Antoine Drieu: Washington University in St Louis
Siling Du: Washington University in St Louis
Steffen E. Storck: Washington University in St Louis
Justin Rustenhoven: Washington University in St Louis
Zachary Papadopoulos: Washington University in St Louis
Taitea Dykstra: Washington University in St Louis
Fenghe Zhong: Washington University in St Louis
Kyungdeok Kim: Washington University in St Louis
Susan Blackburn: Washington University in St Louis
Tornike Mamuladze: Washington University in St Louis
Oscar Harari: Washington University in St Louis
Celeste M. Karch: Washington University in St Louis
Randall J. Bateman: Washington University in St Louis
Richard Perrin: Washington University in St Louis
Martin Farlow: Indiana School of Medicine
Jasmeer Chhatwal: Massachusetts General Hospital, Harvard Medical School
Song Hu: Washington University in St Louis
Gwendalyn J. Randolph: Washington University in St Louis
Igor Smirnov: Washington University in St Louis
Jonathan Kipnis: Washington University in St Louis

Nature, 2022, vol. 611, issue 7936, 585-593

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05397-3

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