Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome

Abstract Once activated, the intracellular receptor NLRP3 assembles an inflammasome protein complex that facilitates the caspase-1-mediated maturation of IL-1β and IL-18. Inactive NLRP3 is guarded by a protein complex containing Hsp90. In response to stress stimuli, Hsp90 is released, and NLRP3 can...

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Autores principales:	Niina Piippo, Eveliina Korhonen, Maria Hytti, Heli Skottman, Kati Kinnunen, Natasha Josifovska, Goran Petrovski, Kai Kaarniranta, Anu Kauppinen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/39138ab7215940c2b80c6676a9f71883
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spelling	oai:doaj.org-article:39138ab7215940c2b80c6676a9f718832021-12-02T11:41:03ZHsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome10.1038/s41598-018-25123-22045-2322https://doaj.org/article/39138ab7215940c2b80c6676a9f718832018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25123-2https://doaj.org/toc/2045-2322Abstract Once activated, the intracellular receptor NLRP3 assembles an inflammasome protein complex that facilitates the caspase-1-mediated maturation of IL-1β and IL-18. Inactive NLRP3 is guarded by a protein complex containing Hsp90. In response to stress stimuli, Hsp90 is released, and NLRP3 can be activated to promote inflammation. In this study, we blocked Hsp90 with geldanamycin and studied the fate of NLRP3 in human retinal pigment epithelial (RPE) cells. RPE cells play a central role in the development of age-related macular degeneration (AMD), a progressive eye disease causing severe vision loss in the elderly. IL-1α-primed ARPE-19 cells, human embryonal stem cell (hESC)-derived RPE cells, and primary human RPE cells were exposed to MG-132 and bafilomycin A to activate NLRP3 via the inhibition of proteasomes and autophagy, respectively. Additionally, RPE cells were treated with geldanamycin at different time points and the levels of NLRP3 and IL-1β were determined. Caspase-1 activity was measured using a commercial assay. Geldanamycin prevented the activation of the inflammasome in human RPE cells. NLRP3 released from its protective complex became degraded by autophagy or secreted from the cells. Controlled destruction of NLRP3 is a potential way to regulate the inflammation associated with chronic diseases, such as AMD.Niina PiippoEveliina KorhonenMaria HyttiHeli SkottmanKati KinnunenNatasha JosifovskaGoran PetrovskiKai KaarnirantaAnu KauppinenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Niina Piippo Eveliina Korhonen Maria Hytti Heli Skottman Kati Kinnunen Natasha Josifovska Goran Petrovski Kai Kaarniranta Anu Kauppinen Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
description	Abstract Once activated, the intracellular receptor NLRP3 assembles an inflammasome protein complex that facilitates the caspase-1-mediated maturation of IL-1β and IL-18. Inactive NLRP3 is guarded by a protein complex containing Hsp90. In response to stress stimuli, Hsp90 is released, and NLRP3 can be activated to promote inflammation. In this study, we blocked Hsp90 with geldanamycin and studied the fate of NLRP3 in human retinal pigment epithelial (RPE) cells. RPE cells play a central role in the development of age-related macular degeneration (AMD), a progressive eye disease causing severe vision loss in the elderly. IL-1α-primed ARPE-19 cells, human embryonal stem cell (hESC)-derived RPE cells, and primary human RPE cells were exposed to MG-132 and bafilomycin A to activate NLRP3 via the inhibition of proteasomes and autophagy, respectively. Additionally, RPE cells were treated with geldanamycin at different time points and the levels of NLRP3 and IL-1β were determined. Caspase-1 activity was measured using a commercial assay. Geldanamycin prevented the activation of the inflammasome in human RPE cells. NLRP3 released from its protective complex became degraded by autophagy or secreted from the cells. Controlled destruction of NLRP3 is a potential way to regulate the inflammation associated with chronic diseases, such as AMD.
format	article
author	Niina Piippo Eveliina Korhonen Maria Hytti Heli Skottman Kati Kinnunen Natasha Josifovska Goran Petrovski Kai Kaarniranta Anu Kauppinen
author_facet	Niina Piippo Eveliina Korhonen Maria Hytti Heli Skottman Kati Kinnunen Natasha Josifovska Goran Petrovski Kai Kaarniranta Anu Kauppinen
author_sort	Niina Piippo
title	Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
title_short	Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
title_full	Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
title_fullStr	Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
title_full_unstemmed	Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome
title_sort	hsp90 inhibition as a means to inhibit activation of the nlrp3 inflammasome
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/39138ab7215940c2b80c6676a9f71883
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Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome

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