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

Nature Medicine volume 23, pages 997–1003 (2017)Cite this article

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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 system1. 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 techniques2. 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.

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Figure 1: IVH triggers inflammation-dependent and bumetanide-sensitive hypersecretion of CSF by the CPE.
Figure 2: CSF hypersecretion after IVH is dependent on inflammation-induced phosphoactivation of the SPAK–NKCC1 complex in the CPE.
Figure 3: TLR4–NF-κB signaling is required for the IVH-induced CSH hypersecretion mediated by upregulated SPAK–NKCC1 complex.

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Acknowledgements

We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute.

Author information

Author notes

  1. Jason K Karimy, Jinwei Zhang, J Marc Simard and Kristopher T Kahle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA

    Jason K Karimy, Jinwei Zhang, Daniel Duran, Charuta Gavankar Furey, M Shahid Mansuri, Julio Montejo, Alberto Vera, Michael L DiLuna, Murat Gunel & Kristopher T Kahle

  2. Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, UK

    Jinwei Zhang

  3. Department of Neurosurgery, University of Maryland, School of Medicine, Baltimore, Maryland, USA

    David B Kurland, Brianna Carusillo Theriault, Jesse A Stokum, Volodymyr Gerzanich & J Marc Simard

  4. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Xu Zhou & Ruslan Medzhitov

  5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Xu Zhou & Ruslan Medzhitov

  6. Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Eric Delpire

  7. Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Seth L Alper

  8. Department of Medicine, Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Seth L Alper

  9. Department of Pathology, University of Maryland, School of Medicine, Baltimore, Maryland, USA

    J Marc Simard

  10. Department of Physiology, University of Maryland, School of Medicine, Baltimore, Maryland, USA

    J Marc Simard

  11. Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA

    Kristopher T Kahle

  12. Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA

    Kristopher T Kahle

  13. Center for Mendelian Genomics, Yale School of Medicine, New Haven, Connecticut, USA

    Kristopher T Kahle

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Contributions

K.T.K., J.M.S., V.G., and J.K.K. conceived and designed the study. J.K.K., J.Z., D.B.K., B.C.T., and J.A.S. preformed molecular and physiological experiments, data analysis for IVH surgery, genetic and pharmacological drug treatment, CSF secretion measurement, and western blot, IHC, and ventricular volume analyses. K.T.K., J.M.S., J.Z., D.D., C.G.F., and J.K.K. drafted the manuscript and figures. X.Z., M.S.M., J.M., A.V., M.L.D., E.D., S.L.A., M.G., and R.M. provided expertise and collaboration in drafting the manuscript. All authors contributed to critical editing and data presentation within the manuscript. J.M.S. and K.T.K. are the principal investigators and are responsible for the oversight of this study.

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Correspondence to Kristopher T Kahle.

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The authors declare no competing financial interests.

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Karimy, J., Zhang, J., Kurland, D. et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med 23, 997–1003 (2017). https://doi.org/10.1038/nm.4361

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