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    The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

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    Authors
    Robert, Stephanie M
    Reeves, 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
    Show allShow less
    Student Authors
    Philip Feinberg
    Academic Program
    MD/PhD
    UMass Chan Affiliations
    Brudnick Neuropsychiatric Research Institute
    Morningside Graduate School of Biomedical Sciences
    Neurobiology
    Schafer Lab
    Document Type
    Journal Article
    Publication Date
    2023-02-16
    Keywords
    CSF
    NKCC1
    SPAK
    blood-CSF barrier
    cerebrospinal fluid
    choroid plexus
    hydrocephalus
    neuro-inflammation
    
    Metadata
    Show full item record
    Link to Full Text
    https://doi.org/10.1016/j.cell.2023.01.017
    Abstract
    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.2023.01.017
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51862
    PubMed ID
    36803604
    Rights
    Copyright © 2023 Elsevier Inc. All rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.cell.2023.01.017
    Scopus Count
    Collections
    Morningside Graduate School of Biomedical Sciences Scholarly Publications
    Neurobiology Student Publications
    Neurobiology Faculty Publications

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