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Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

2022; Nature Portfolio; Volume: 611; Issue: 7936 Linguagem: Inglês

10.1038/s41586-022-05397-3

1476-4687

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 J. Perrin, Martin R. Farlow, Jasmeer P. Chhatwal, Jared R. Brosch, Jill Buck, Marty Farlow, Bernardino Ghetti, Sarah Adams, Nicolas R. Barthélemy, Tammie L.S. Benzinger, Susan E. Brandon, Virginia Buckles, Lisa Cash, Charlie Chen, Jasmin Chua, Carlos Cruchaga, Darcy Denner, Aylin Dincer, Tamara Donahue, Anne M. Fagan, Becca Feldman, Shaney Flores, Erin Franklin, Nelly Joseph‐Mathurin, Alyssa Gonzalez, Brian A. Gordon, Julia Gray, Emily Gremminger, Alex Groves, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, David M. Holtzman, Russ C. Hornbeck, Gina Jerome, Sarah Keefe, Deb Koudelis, Yan Li, Jacob I. Marsh, Rita Martinez, Kwasi G. Mawuenyega, Austin McCullough, Eric McDade, John Morris, Joanne Norton, Kristine Shady, Wendy Sigurdson, Jennifer A. Smith, Peter Wang, Qing Wang, Chengjie Xiong, Jinbin Xu, Xu Xiong, Ricardo Allegri, Patricio Chrem Méndez, Noelia Egido, Aki Araki, Takeshi Ikeuchi, Kenji Ishii, Kensaku Kasuga, Jacob Bechara, W. K. Brooks, Peter R. Schofield, Sarah Berman, Sarah B. Goldberg, Snežana Ikonomović, William E. Klunk, Oscar L. López, James M. Mountz, Neelesh K. Nadkarni, Riddhi Patira, Lori Smith, Beth E. Snitz, Sarah Thompson, Elise A. Weamer, Courtney Bodge, Stephen Salloway, Kathleen Carter, Duc M. Duong, Erik C. B. Johnson, Allan I. Levey, Lingyan Ping, Nicholas T. Seyfried, Colleen Fitzpatrick, Helena C. Chui, John M. Ringman, Gregory S. Day, Neill R. Graff‐Radford, Morgan Graham, Sochenda Stephens, Chrismary De La Cruz, Jill Goldman, Arlene Mejia, Katie Neimeyer, James Noble, Anna Diffenbacher, Igor Yakushev, Johannes Levin, Jonathan Vöglein, J. Maxwell Douglas, Nick C. Fox, Miguel L. Grilo, Cath Mummery, Antoinette O’Connor, Bianca Esposito, Alison Goate, Alan E. Renton, Hisako Fujii, Michio Senda, Hiroyuki Shimada, Samantha L. Gardener, Ralph N. Martins, Hamid R. Sohrabi, Kevin Taddei, Susanne Gräber‐Sultan, Lisa M. Häsler, Anna Hofmann, Mathias Jucker, Stephan Käser, Elke Kuder-Buletta, Christoph Laske, Oliver Preische, Christian Haass, Estrella Morenas‐Rodríguez, Brigitte Nuscher, Ryoko Ihara, Akemi Nagamatsu, Yoshiki Niimi, Clifford R. Jack, Robert A. Koeppe, Neal Scott Mason, Colin L. Masters, Ulricke Obermüller, Song Hu, Gwendalyn J. Randolph, Igor Smirnov, Jonathan Kipnis,

Neonatal and fetal brain pathology

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. Perivascular and leptomeningeal macrophages, collectively termed here parenchymal border macrophages, are shown to regulate flow dynamics of cerebrospinal fluid, implicating this cell population as new therapeutic targets in neurological diseases such as Alzheimer's.