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Nat Med. 2017 Aug;23(8):997-1003. doi: 10.1038/nm.4361. Epub 2017 Jul 10.

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.

Author information

1
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
2
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, UK.
3
Department of Neurosurgery, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
4
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
6
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
7
Division of Nephrology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
8
Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
9
Department of Pathology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
10
Department of Physiology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
11
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
12
Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA.
13
Center for Mendelian Genomics, Yale School of Medicine, New Haven, Connecticut, USA.

Abstract

The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.

PMID:
28692063
DOI:
10.1038/nm.4361
[Indexed for MEDLINE]

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