Inflammatory Mediators in Hydrocephalus: A Study of the Activation of an Electrolyte Transporter, TRPV4

Hydrocephalus is caused by the abnormal accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain due to overproduction, malabsorption or blockage in CSF flow. The choroid plexus is a complex network of fenestrated capillaries surrounded by a monolayer of cuboidal cells called the choroid plexus epithelium (CPE) which generates 500-600 mL of CSF daily. Composition and production of CSF are regulated by ion transporters, channels and pumps which are located in either the apical or basolateral membranes of the CPE. Transient receptor potential vanilloid 4 (TRPV4) is a calcium and sodium permeable cation channel found on the apical membrane of the CPE. The channel can be activated by changes in osmotic balance (hypotonicity), temperature, mechanical stress (pressure), and inflammatory mediators. Our laboratory has demonstrated that activation of TRPV4 is affected by inflammatory mediators (1) and that treatment with TRPV4 antagonists can alleviate hydrocephalic progression (2). Inflammation is well documented in all forms of hydrocephalus as a primary or secondary consequence of its pathophysiology. CPE is exposed to inflammatory mediators in the CSF after infection or injury. We hypothesize that inflammatory mediators can directly act on CPE and alter transepithelial fluid and electrolyte flux. The inflammatory mediator lipopolysaccharide (LPS, 10 ng/ml) was added to the human choroid plexus papilloma cell line (HIBCPP) to mimic bacterial infection. The activation of TRPV4, a channel implicated in CSF production under stress conditions, was detected by Ussing-style electrophysiology to quantify the amount of net transepithelial electrolyte flux (short-circuit current (SCC) and changes in transepithelial permeability (transepithelial resistance) in the cultures. After a 10 or 30 min preincubation with an inflammatory mediator, TRPV4 agonist GSK1016790A (GSK) was used to stimulate the ion influx into the cells. For each treatment group, statistical significance was analyzed using a multiple t-test. After 10 minutes of preincubation, LPS (10 ng/ml) appears to potentiate individual components of a multiphasic TRPV4-mediated transepithelial electrolyte flux. The 10-minute LPS preincubation did not alter the TRPV4-mediated increase in transepithelial conductance. After 30 minutes of preincubation the LPS effect is extended to several components of TRPV4-stimulated electrolyte flux and there is a potentiation of the TRPV4-induced increase in transepithelial conductance. This suggests that inflammation would have a significant impact on transepithelial ionic transport and permeability upon extended exposure to an inflammatory stimulant. These data indicate a functional interaction between TRPV4 and inflammatory mechanisms. References 1. Simpson, S. et al. (2019). Am J Physiol Cell Physiol 317, C881-C893. 2. Hochstetler, A.E. et al. (2020). JCI Insight 5, 1-14. These studies were supported by DoD Congressionally Directed Medical Research Program Grants #HT94252310296 and #HT94252310401 (BBY) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.