The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

Stephanie M. Robert; Benjamin C. Reeves; Emre Kiziltug; Phan Q. Duy; Jason K. Karimy; M. Shahid Mansuri; Arnaud Marlier; Garrett Allington; Ana B.W. Greenberg; Tyrone DeSpenza; Amrita K. Singh; Xue Zeng; Kedous Y. Mekbib; Adam J. Kundishora; Carol Nelson-Williams; Le Thi Hao; Jinwei Zhang; Tu Kiet T. Lam; Rashaun Wilson; William E. Butler; Michael L. Diluna; Philip Feinberg; Dorothy P. Schafer; Kiavash Movahedi; Allen Tannenbaum; Sunil Koundal; Xinan Chen; Helene Benveniste; David D. Limbrick; Steven J. Schiff; Bob S. Carter; Murat Gunel; J. Marc Simard; Richard P. Lifton; Seth L. Alper; Eric Delpire; Kristopher T. Kahle

doi:10.1016/j.cell.2023.01.017

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

Stephanie M. Robert, Benjamin C. Reeves, Emre Kiziltug, Phan Q. Duy, Jason K. Karimy, M. Shahid Mansuri, Arnaud Marlier, Garrett Allington, Ana B.W. Greenberg, Tyrone DeSpenza, Amrita K. Singh, Xue Zeng, Kedous Y. Mekbib, Adam J. Kundishora, Carol Nelson-Williams, Le Thi Hao, Jinwei Zhang, Tu Kiet T. Lam, Rashaun Wilson, William E. ButlerMichael L. Diluna, Philip Feinberg, Dorothy P. Schafer, Kiavash Movahedi, Allen Tannenbaum, Sunil Koundal, Xinan Chen, Helene Benveniste, David D. Limbrick, Steven J. Schiff, Bob S. Carter, Murat Gunel, J. Marc Simard, Richard P. Lifton, Seth L. Alper, Eric Delpire, Kristopher T. Kahle

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56 Scopus citations

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.

Original language	English
Pages (from-to)	764-785.e21
Journal	Cell
Volume	186
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2023.01.017
State	Published - Feb 16 2023

Keywords

CSF
NKCC1
SPAK
blood-CSF barrier
cerebrospinal fluid
choroid plexus
hydrocephalus
neuro-inflammation

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10.1016/j.cell.2023.01.017

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Robert, S. M., Reeves, B. C., Kiziltug, E., Duy, P. Q., Karimy, J. K., Mansuri, M. S., Marlier, A., Allington, G., Greenberg, A. B. W., DeSpenza, T., Singh, A. K., Zeng, X., Mekbib, K. Y., Kundishora, A. J., Nelson-Williams, C., Hao, L. T., Zhang, J., Lam, T. K. T., Wilson, R., ... Kahle, K. T. (2023). The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell, 186(4), 764-785.e21. https://doi.org/10.1016/j.cell.2023.01.017

@article{8aa02c08eed341c88dd404b1914ac13e,

title = "The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus",

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.",

keywords = "CSF, NKCC1, SPAK, blood-CSF barrier, cerebrospinal fluid, choroid plexus, hydrocephalus, neuro-inflammation",

author = "Robert, {Stephanie M.} and Reeves, {Benjamin C.} and Emre Kiziltug and Duy, {Phan Q.} and Karimy, {Jason K.} and Mansuri, {M. Shahid} and Arnaud Marlier and Garrett Allington and Greenberg, {Ana B.W.} and Tyrone DeSpenza and Singh, {Amrita K.} and Xue Zeng and Mekbib, {Kedous Y.} and Kundishora, {Adam J.} and Carol Nelson-Williams and Hao, {Le Thi} and Jinwei Zhang and Lam, {Tu Kiet T.} and Rashaun Wilson and Butler, {William E.} and Diluna, {Michael L.} and Philip Feinberg and Schafer, {Dorothy P.} and Kiavash Movahedi and Allen Tannenbaum and Sunil Koundal and Xinan Chen and Helene Benveniste and Limbrick, {David D.} and Schiff, {Steven J.} and Carter, {Bob S.} and Murat Gunel and Simard, {J. Marc} and Lifton, {Richard P.} and Alper, {Seth L.} and Eric Delpire and Kahle, {Kristopher T.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = feb,

day = "16",

doi = "10.1016/j.cell.2023.01.017",

language = "English",

volume = "186",

pages = "764--785.e21",

journal = "Cell",

issn = "0092-8674",

number = "4",

}

Robert, SM, Reeves, BC, Kiziltug, E, Duy, PQ, Karimy, JK, Mansuri, MS, Marlier, A, Allington, G, Greenberg, ABW, DeSpenza, T, Singh, AK, Zeng, X, Mekbib, KY, Kundishora, AJ, Nelson-Williams, C, Hao, LT, Zhang, J, Lam, TKT, Wilson, R, Butler, WE, Diluna, ML, Feinberg, P, Schafer, DP, Movahedi, K, Tannenbaum, A, Koundal, S, Chen, X, Benveniste, H, Limbrick, DD, Schiff, SJ, Carter, BS, Gunel, M, Simard, JM, Lifton, RP, Alper, SL, Delpire, E & Kahle, KT 2023, 'The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus', Cell, vol. 186, no. 4, pp. 764-785.e21. https://doi.org/10.1016/j.cell.2023.01.017

TY - JOUR

T1 - The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

AU - Robert, Stephanie M.

AU - Reeves, Benjamin C.

AU - Kiziltug, Emre

AU - Duy, Phan Q.

AU - Karimy, Jason K.

AU - Mansuri, M. Shahid

AU - Marlier, Arnaud

AU - Allington, Garrett

AU - Greenberg, Ana B.W.

AU - DeSpenza, Tyrone

AU - Singh, Amrita K.

AU - Zeng, Xue

AU - Mekbib, Kedous Y.

AU - Kundishora, Adam J.

AU - Nelson-Williams, Carol

AU - Hao, Le Thi

AU - Zhang, Jinwei

AU - Lam, Tu Kiet T.

AU - Wilson, Rashaun

AU - Butler, William E.

AU - Diluna, Michael L.

AU - Feinberg, Philip

AU - Schafer, Dorothy P.

AU - Movahedi, Kiavash

AU - Tannenbaum, Allen

AU - Koundal, Sunil

AU - Chen, Xinan

AU - Benveniste, Helene

AU - Limbrick, David D.

AU - Schiff, Steven J.

AU - Carter, Bob S.

AU - Gunel, Murat

AU - Simard, J. Marc

AU - Lifton, Richard P.

AU - Alper, Seth L.

AU - Delpire, Eric

AU - Kahle, Kristopher T.

PY - 2023/2/16

Y1 - 2023/2/16

N2 - 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.

AB - 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.

KW - CSF

KW - NKCC1

KW - SPAK

KW - blood-CSF barrier

KW - cerebrospinal fluid

KW - choroid plexus

KW - hydrocephalus

KW - neuro-inflammation

UR - http://www.scopus.com/inward/record.url?scp=85147985280&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.01.017

DO - 10.1016/j.cell.2023.01.017

M3 - Article

C2 - 36803604

AN - SCOPUS:85147985280

SN - 0092-8674

VL - 186

SP - 764-785.e21

JO - Cell

JF - Cell

IS - 4

ER -

The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

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Keywords

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