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.

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Citation

Published Version (Please cite this version)

10.3389/fmolb.2022.971219

Publication Info

Swenson-Fields, Katherine I, Christopher J Ward, Micaila E Lopez, Shaneann Fross, Anna L Heimes Dillon, James D Meisenheimer, Adib J Rabbani, Emily Wedlock, et al. (2022). Caspase-1 and the inflammasome promote polycystic kidney disease progression. Frontiers in molecular biosciences, 9. p. 971219. 10.3389/fmolb.2022.971219 Retrieved from https://hdl.handle.net/10161/26399.

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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 Roses and colleagues found to a susceptibility factor for the presence of AD. Currently, our data are pointing to a relationship between apoE and oxidative stress where apoE appears to modulate nitric oxide production in a species specific manner. To further test this idea, we have created transgenic mice expressing the entire human NOS2 gene which will now be tested in various models of neurodegeneration and inflammation. Similarly, we are developing transgenic animals which express the human TAU gene. When properly stressed, these TAU-transgenic animals may display the neurofibrillary tangle pathology which is associated with neurodegeneration in a wide variety of neurological diseases.

If our transgenic animals prove to be validated models of human
disease, then the process to screen for chemicals which might alter the disease outcome in those models can begin in earnest. Should compounds be identified, then the various phases of clinical trials may proceed.

At present, my community service includes participation on the Alzheimer's Association Medical and Scientific Advisory Board and on the Neurological Sciences III Study Section for the National Institutes of Health extramural research program. I have previously served in a similar capacity for the American Health Assistance Foundation and the Long Island Alzheimer's Foundation. I have also had the pleasure to serve as a scientific consultant for various biotechnology companies.

Keywords: Neurodegeneration, Alzheimer's, Transgenic, Animal Models, Amyloid, Apolipoprotein-E, Molecular Biology, Biochemistry


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