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 Jr; Amrita K Singh; Xue Zeng; Kedous Y Mekbib; Adam J Kundishora; Carol Nelson-Williams; Le Thi Hao; Jinwei Zhang; TuKiet 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 Jr; 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

Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017.

Authors

Stephanie M Robert¹, Benjamin C Reeves¹, Emre Kiziltug¹, Phan Q Duy¹, Jason K Karimy¹, M Shahid Mansuri², Arnaud Marlier¹, Garrett Allington³, Ana B W Greenberg¹, Tyrone DeSpenza Jr¹, Amrita K Singh¹, Xue Zeng¹, Kedous Y Mekbib¹, Adam J Kundishora¹, Carol Nelson-Williams¹, Le Thi Hao¹, Jinwei Zhang⁴, TuKiet T Lam⁵, Rashaun Wilson⁵, William E Butler⁶, Michael L Diluna¹, Philip Feinberg⁷, Dorothy P Schafer⁸, Kiavash Movahedi⁹, Allen Tannenbaum¹⁰, Sunil Koundal¹¹, Xinan Chen¹², Helene Benveniste¹¹, David D Limbrick Jr¹³, Steven J Schiff¹, Bob S Carter⁶, Murat Gunel¹, J Marc Simard¹⁴, Richard P Lifton¹⁵, Seth L Alper¹⁶, Eric Delpire¹⁷, Kristopher T Kahle¹⁸

Affiliations

¹ Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA.
² Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
⁴ Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter EX1 2LU, UK.
⁵ Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA; Keck MS & Proteomics Resource, Yale University School of Medicine, New Haven, CT 06520, USA.
⁶ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Medical Scientist Training Program, UMass Chan Medical School, Worcester, MA 01655, USA.
⁸ Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
⁹ Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium.
¹⁰ Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York City, NY 11794, USA.
¹¹ Department of Anesthesiology, Yale School of Medicine, New Haven, CT 06520, USA.
¹² Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA.
¹³ Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁴ Department of Neurosurgery, University of Maryland, School of Medicine, Baltimore, MD 21201, USA; Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA; Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
¹⁵ Laboratory of Human Genetics and Genomics, the Rockefeller University, New York, NY 10065, USA.
¹⁶ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁷ Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
¹⁸ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA; Department of Neurosurgery and Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. Electronic address: kahle.kristopher@mgh.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Blood-Brain Barrier / metabolism
Brain / metabolism
Choroid Plexus* / metabolism
Cytokine Release Syndrome / pathology
Humans
Hydrocephalus* / cerebrospinal fluid
Hydrocephalus* / immunology
Immunity, Innate

Abstract

Publication types

MeSH terms

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