Robert, Stephanie MReeves, Benjamin CKiziltug, EmreDuy, Phan QKarimy, Jason KMansuri, M ShahidMarlier, ArnaudAllington, GarrettGreenberg, Ana B WDeSpenza, TyroneSingh, Amrita KZeng, XueMekbib, Kedous YKundishora, Adam JNelson-Williams, CarolHao, Le ThiZhang, JinweiLam, TuKiet TWilson, RashaunButler, William EDiluna, Michael LFeinberg, Philip ASchafer, Dorothy PMovahedi, KiavashTannenbaum, AllenKoundal, SunilChen, XinanBenveniste, HeleneLimbrick, David DSchiff, Steven JCarter, Bob SGunel, MuratSimard, J MarcLifton, Richard PAlper, Seth LDelpire, EricKahle, Kristopher T2023-03-202023-03-202023-02-16Robert 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: 36803604.1097-417210.1016/j.cell.2023.01.01736803604https://hdl.handle.net/20.500.14038/51862The 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.enCopyright © 2023 Elsevier Inc. All rights reserved.CSFNKCC1SPAKblood-CSF barriercerebrospinal fluidchoroid plexushydrocephalusneuro-inflammationJournal ArticleCell