The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.
CSF
NKCC1
SPAK
blood-CSF barrier
cerebrospinal fluid
choroid plexus
hydrocephalus
neuro-inflammation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
16 02 2023
16 02 2023
Historique:
received:
01
01
2022
revised:
26
09
2022
accepted:
12
01
2023
pmc-release:
16
02
2024
entrez:
21
2
2023
pubmed:
22
2
2023
medline:
25
2
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36803604
pii: S0092-8674(23)00047-8
doi: 10.1016/j.cell.2023.01.017
pmc: PMC10069664
mid: NIHMS1875780
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
764-785.e21Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109358
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS111029
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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