ALERT: This system is being upgraded on Tuesday December 12. It will not be available
for use for several hours that day while the upgrade is in progress. Deposits to DukeSpace
will be disabled on Monday December 11, so no new items are to be added to the repository
while the upgrade is in progress. Everything should be back to normal by the end of
day, December 12.
Caspase-1 and the inflammasome promote polycystic kidney disease progression.
Abstract
We and others have previously shown that the presence of renal innate immune cells
can promote polycystic kidney disease (PKD) progression. In this study, we examined
the influence of the inflammasome, a key part of the innate immune system, on PKD.
The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds
to stimuli like cellular damage or microbes by activating Caspase-1, and generating
critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide
evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors
were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys
from both orthologous (PKD1 RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated
in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily
in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease
progression in female mice, implying sex-specific differences in the renal immune
environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism
underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally,
treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug
that has been shown to inhibit the inflammasome, protected renal function specifically
in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively,
these results provide evidence for the first time that the activated Caspase-1/inflammasome
promotes cyst expansion and disease progression in PKD, particularly in females. Moreover,
the data suggest that this innate immune pathway may be a relevant target for therapy
in PKD.
Type
Journal articlePermalink
https://hdl.handle.net/10161/26399Published Version (Please cite this version)
10.3389/fmolb.2022.971219Publication Info
Swenson-Fields, Katherine I; Ward, Christopher J; Lopez, Micaila E; Fross, Shaneann;
Heimes Dillon, Anna L; Meisenheimer, James D; ... Fields, Timothy A (2022). Caspase-1 and the inflammasome promote polycystic kidney disease progression. Frontiers in molecular biosciences, 9. pp. 971219. 10.3389/fmolb.2022.971219. Retrieved from https://hdl.handle.net/10161/26399.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Michael P. Vitek
Adjunct Associate Professor in Neurology
The overall interest of my laboratory is to identify the underlying causes of neurodegenerative
diseases such as Alzheimer's disease. Once causes or experimental endpoints are determined,
then strategies to find chemicals which can ameliorate pathophysiological events can
be devised. In general, we are working to create transgenic animals and validate them
as models of human disease. Our specific approach has been to study the function
of apolipoprotein-E (apoE) which Roses and coll

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info