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Caspase-1 and the inflammasome promote polycystic kidney disease progression.

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Date
2022-01
Authors
Swenson-Fields, Katherine I
Ward, Christopher J
Lopez, Micaila E
Fross, Shaneann
Heimes Dillon, Anna L
Meisenheimer, James D
Rabbani, Adib J
Wedlock, Emily
Basu, Malay K
Jansson, Kyle P
Rowe, Peter S
Stubbs, Jason R
Wallace, Darren P
Vitek, Michael P
Fields, Timothy A
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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 article
Subject
Caspase-1
IL-18
IL-1β
MYC
YAP
hydroxychloroquine
inflammasome
polycystic kidney disease
Permalink
https://hdl.handle.net/10161/26399
Published Version (Please cite this version)
10.3389/fmolb.2022.971219
Publication 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.
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Scholars@Duke

Vitek

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
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