The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus
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Authors
Robert, Stephanie MReeves, Benjamin C
Kiziltug, Emre
Duy, Phan Q
Karimy, Jason K
Mansuri, M Shahid
Marlier, Arnaud
Allington, Garrett
Greenberg, Ana B W
DeSpenza, Tyrone
Singh, Amrita K
Zeng, Xue
Mekbib, Kedous Y
Kundishora, Adam J
Nelson-Williams, Carol
Hao, Le Thi
Zhang, Jinwei
Lam, TuKiet T
Wilson, Rashaun
Butler, William E
Diluna, Michael L
Feinberg, Philip
Schafer, Dorothy P
Movahedi, Kiavash
Tannenbaum, Allen
Koundal, Sunil
Chen, Xinan
Benveniste, Helene
Limbrick, David D
Schiff, Steven J
Carter, Bob S
Gunel, Murat
Simard, J Marc
Lifton, Richard P
Alper, Seth L
Delpire, Eric
Kahle, Kristopher T
Student Authors
Philip FeinbergAcademic Program
MD/PhDUMass Chan Affiliations
Brudnick Neuropsychiatric Research InstituteMorningside Graduate School of Biomedical Sciences
Neurobiology
Schafer Lab
Document Type
Journal ArticlePublication Date
2023-02-16Keywords
CSFNKCC1
SPAK
blood-CSF barrier
cerebrospinal fluid
choroid plexus
hydrocephalus
neuro-inflammation
Metadata
Show full item recordAbstract
The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.Source
Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, Kahle KT. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017. PMID: 36803604.DOI
10.1016/j.cell.2023.01.017Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51862PubMed ID
36803604Rights
Copyright © 2023 Elsevier Inc. All rights reserved.ae974a485f413a2113503eed53cd6c53
10.1016/j.cell.2023.01.017