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

Autor:	Swenson-Fields KI; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States., Ward CJ; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, United States., Lopez ME; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States., Fross S; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States., Heimes Dillon AL; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States., Meisenheimer JD; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States., Rabbani AJ; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States., Wedlock E; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States., Basu MK; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States., Jansson KP; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, United States., Rowe PS; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, United States., Stubbs JR; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, United States., Wallace DP; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, United States., Vitek MP; Duke University Medical Center, Durham, NC, United States.; Resilio Therapeutics LLC, Durham, NC, United States., Fields TA; The Jared J. Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, United States.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2022 Nov 29; Vol. 9, pp. 971219. Date of Electronic Publication: 2022 Nov 29 (Print Publication: 2022).
DOI:	10.3389/fmolb.2022.971219
Abstrakt:	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. Competing Interests: Author MV was employed by the company Resilio Therapeutics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Swenson-Fields, Ward, Lopez, Fross, Heimes Dillon, Meisenheimer, Rabbani, Wedlock, Basu, Jansson, Rowe, Stubbs, Wallace, Vitek and Fields.)
Databáze:	MEDLINE
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