Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Fluids and Barriers of the CNS
Published in: Fluids and Barriers of the CNS 1/2023

Open Access 01-12-2023 | Hydrocephalus | Research

In vitro investigation of the effect of proinflammatory cytokines on mouse choroid plexus membrane transporters Ncbe and NKCC1

Authors: Laura Øllegaard Johnsen, Kathrine Abildskov Friis, Helle Hasager Damkier

Published in: Fluids and Barriers of the CNS | Issue 1/2023

Login to get access

Abstract

Intraventricular hemorrhage is a potentially life-threatening condition. Approximately 20% of patients develop posthemorrhagic hydrocephalus with increased ventricular volume and intracranial pressure. Hydrocephalus develops partially due to increased secretion of cerebrospinal fluid by the choroid plexus. During hemorrhage a multitude of factors are released into the cerebrospinal fluid. Many of these have been implicated in the hypersecretion. In this study, we have investigated the isolated effect of inflammatory components, on the abundance of two membrane transporters involved in cerebrospinal fluid secretion by the choroid plexus: the Na+-dependent Cl−/HCO3− exchanger, Ncbe, and the Na+, K+, 2Cl− cotransporter, NKCC1. We have established a primary choroid plexus epithelial cell culture from 1 to 7 days old mouse pups. Seven days after seeding, the cells formed a monolayer. The cells were treated with either tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), or interleukin 6 (IL-6) to mimic inflammation. The data show that treatment with TNFα, and IL-1β only transiently increased NKCC1 abundance whereas the effect on Ncbe abundance was a transient decrease. IL-6 however significantly increased NKCC1 (242%), the phosphorylated NKCC1 (147%), as well as pSPAK (406%) abundance, but had no effect on Ncbe. This study suggests that the inflammatory pathway involved in hypersecretion primarily is mediated by activation of basolateral receptors in the choroid plexus, mainly facilitated by IL-6. This study highlights the complexity of the pathophysiological circumstances occurring during intraventricular hemorrhage.
Literature
1.
2.
Adams HP Jr., Kassell NF, Torner JC. Usefulness of computed tomography in predicting outcome after aneurysmal subarachnoid hemorrhage: a preliminary report of the Cooperative Aneurysm Study. Neurology. 1985;35(9):1263–7.CrossRefPubMed
3.
Chen S, Luo J, Reis C, Manaenko A, Zhang J. Hydrocephalus after Subarachnoid Hemorrhage: pathophysiology, diagnosis, and treatment. Biomed Res Int. 2017;2017:8584753.PubMedPubMedCentral
4.
Kahle KT, Kulkarni AV, Limbrick DD Jr., Warf BC. Hydrocephalus in children. Lancet. 2016;387(10020):788–99.CrossRefPubMed
5.
Kanat A, Turkmenoglu O, Aydin MD, Yolas C, Aydin N, Gursan N, et al. Toward changing of the pathophysiologic basis of acute hydrocephalus after subarachnoid hemorrhage: a preliminary experimental study. World Neurosurg. 2013;80(3–4):390–5.CrossRefPubMed
6.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017;23(8):997–1003.CrossRefPubMed
7.
Devlin P, Ishrat T, Stanfill AG. A systematic review of inflammatory cytokine changes following aneurysmal subarachnoid hemorrhage in animal models and humans. Transl Stroke Res. 2022.
8.
9.
Bian C, Wan Y, Koduri S, Hua Y, Keep RF, Xi G. Iron-Induced Hydrocephalus: the role of Choroid Plexus Stromal Macrophages. Transl Stroke Res. 2022.
10.
Yang TC, Chang CH, Liu YT, Chen YL, Tu PH, Chen HC. Predictors of shunt-dependent chronic hydrocephalus after aneurysmal subarachnoid haemorrhage. Eur Neurol. 2013;69(5):296–303.CrossRefPubMed
11.
Praetorius J, Damkier HH. Transport across the choroid plexus epithelium. Am J Physiol Cell Physiol. 2017;312(6):C673–C86.CrossRefPubMed
12.
Damkier HH, Brown PD, Praetorius J. Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev. 2013;93(4):1847–92.CrossRefPubMed
13.
Bothwell SW, Janigro D, Patabendige A. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids and Barriers of the CNS. 2019;16(1):9.CrossRefPubMedPubMedCentral
14.
Davson H, Segal MB. The effects of some inhibitors and accelerators of sodium transport on the turnover of 22Na in the cerebrospinal fluid and the brain. J Physiol. 1970;209(1):131–53.CrossRefPubMedPubMedCentral
15.
Welch K. Secretion of Cerebrospinal Fluid by Choroid Plexus of the rabbit. Am J Physiol. 1963;205:617–24.CrossRefPubMed
16.
17.
Masuzawa T, Ohta T, Kawamura M, Nakahara N, Sato F. Immunohistochemical localization of Na+, K+-ATPase in the choroid plexus. Brain Res. 1984;302(2):357–62.CrossRefPubMed
18.
Plotkin MD, Kaplan MR, Peterson LN, Gullans SR, Hebert SC, Delpire E. Expression of the Na+-K+-2Cl cotransporter BSC2 in the nervous system. Am J Physiol. 1997;272(1 Pt 1):C173–C83.CrossRefPubMed
19.
Praetorius J, Nielsen S. Distribution of sodium transporters and aquaporin-1 in the human choroid plexus. Am J Physiol Cell Physiol. 2006;291(1):C59–c67.CrossRefPubMed
20.
Javaheri S, Wagner KR. Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system. J Clin Investig. 1993;92(5):2257–61.CrossRefPubMedPubMedCentral
21.
Oernbo EK, Steffensen AB, Razzaghi Khamesi P, Toft-Bertelsen TL, Barbuskaite D, Vilhardt F, et al. Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure. Fluids and Barriers of the CNS. 2022;19(1):65.CrossRefPubMedPubMedCentral
22.
Steffensen AB, Oernbo EK, Stoica A, Gerkau NJ, Barbuskaite D, Tritsaris K, et al. Cotransporter-mediated water transport underlying cerebrospinal fluid formation. Nat Commun. 2018;9(1):2167.CrossRefPubMedPubMedCentral
23.
Gregoriades JMC, Madaris A, Alvarez FJ, Alvarez-Leefmans FJ. Genetic and pharmacologic inactivation of apical NKCC1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter. Am J Physiol Cell Physiol. 2018.
24.
Xu H, Fame RM, Sadegh C, Sutin J, Naranjo C, Della S, et al. Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development. Nat Commun. 2021;12(1):447.CrossRefPubMedPubMedCentral
25.
Jacobs S, Ruusuvuori E, Sipila ST, Haapanen A, Damkier HH, Kurth I, et al. Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci USA. 2008;105(1):311–6.CrossRefPubMed
26.
Li Q, Ding Y, Krafft P, Wan W, Yan F, Wu G et al. Targeting Germinal Matrix Hemorrhage-Induced overexpression of Sodium-Coupled bicarbonate exchanger reduces posthemorrhagic hydrocephalus formation in neonatal rats. J Am Heart Assoc. 2018;7(3).
27.
Luo C, Yao J, Bi H, Li Z, Li J, Xue G, et al. Clinical value of inflammatory cytokines in patients with Aneurysmal Subarachnoid Hemorrhage. Clin Interv Aging. 2022;17:615–26.CrossRefPubMedPubMedCentral
28.
Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, et al. IFN-gamma-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair. Brain. 2013;136(Pt 11):3427–40.CrossRefPubMed
29.
Shimada A, Hasegawa-Ishii S. Increased cytokine expression in the choroid plexus stroma and epithelium in response to endotoxin-induced systemic inflammation in mice. Toxicol Rep. 2021;8:520–8.CrossRefPubMedPubMedCentral
30.
Lolansen SD, Rostgaard N, Barbuskaite D, Capion T, Olsen MH, Norager NH, et al. Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters. Fluids and Barriers of the CNS. 2022;19(1):62.CrossRefPubMedPubMedCentral
31.
Menheniott TR, Charalambous M, Ward A. Derivation of primary choroid plexus epithelial cells from the mouse. Methods Mol Biol. 2010;633:207–20.CrossRefPubMed
32.
Praetorius J, Nejsum LN, Nielsen S. A SCL4A10 gene product maps selectively to the basolateral plasma membrane of choroid plexus epithelial cells. Am J Physiol Cell Physiol. 2004;286(3):C601–10.CrossRefPubMed
33.
Rostgaard N, Olsen MH, Capion T, MacAulay N, Juhler M. Inflammatory markers as predictors of Shunt Dependency and Functional Outcome in patients with Aneurysmal Subarachnoid Hemorrhage. Biomedicines. 2023;11(4).
34.
Stridh L, Ek CJ, Wang X, Nilsson H, Mallard C. Regulation of toll-like receptors in the choroid plexus in the immature brain after systemic inflammatory stimuli. Transl Stroke Res. 2013;4(2):220–7.CrossRefPubMedPubMedCentral
35.
36.
Chaudhry SR, Stoffel-Wagner B, Kinfe TM, Guresir E, Vatter H, Dietrich D et al. Elevated systemic IL-6 levels in patients with Aneurysmal Subarachnoid hemorrhage is an unspecific marker for Post-SAH complications. Int J Mol Sci. 2017;18(12).
37.
Laflamme N, Rivest S. Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J. 2001;15(1):155–63.CrossRefPubMed
38.
Vargas-Caraveo A, Sayd A, Maus SR, Caso JR, Madrigal JLM, Garcia-Bueno B, et al. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci Rep. 2017;7(1):13113.CrossRefPubMedPubMedCentral
39.
Asami A, Kurganov E, Miyata S. Proliferation of endothelial cells in the choroid plexus of normal and hydrocephalic mice. J Chem Neuroanat. 2020;106:101796.CrossRefPubMed
40.
Balusu S, Van Wonterghem E, De Rycke R, Raemdonck K, Stremersch S, Gevaert K, et al. Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Mol Med. 2016;8(10):1162–83.CrossRefPubMedPubMedCentral
41.
Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, et al. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023;186(4):764–85. e21.CrossRefPubMed
42.
Strazielle N, Ghersi-Egea JF. Demonstration of a coupled metabolism-efflux process at the choroid plexus as a mechanism of brain protection toward xenobiotics. J Neuroscience: Official J Soc Neurosci. 1999;19(15):6275–89.CrossRef
Metadata
Title
In vitro investigation of the effect of proinflammatory cytokines on mouse choroid plexus membrane transporters Ncbe and NKCC1
Authors
Laura Øllegaard Johnsen
Kathrine Abildskov Friis
Helle Hasager Damkier
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Fluids and Barriers of the CNS / Issue 1/2023
Electronic ISSN: 2045-8118
DOI
https://doi.org/10.1186/s12987-023-00474-9

Other articles of this Issue 1/2023

Fluids and Barriers of the CNS 1/2023 Go to the issue

Research

Blue light exposure collapses the inner blood-retinal barrier by accelerating endothelial CLDN5 degradation through the disturbance of GNAZ and the activation of ADAM17

Review

Occludin: a gatekeeper of brain Infection by HIV-1

Research

Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus

Research

Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production

Research

Early postnatal microglial ablation in the Ccdc39 mouse model reveals adverse effects on brain development and in neonatal hydrocephalus

Brief Report

Age-appropriate potassium clearance from perinatal cerebrospinal fluid depends on choroid plexus NKCC1