Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease

Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pa...

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Autores principales:	Francesca La Rosa, Roberta Mancuso, Simone Agostini, Federica Piancone, Ivana Marventano, Marina Saresella, Ambra Hernis, Chiara Fenoglio, Daniela Galimberti, Elio Scarpini, Mario Clerici
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Alzheimer’s disease D4T miRNAs NLRP3 inflammasome Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4b94a6bf34874508a18178ee46cdecbb
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spelling	oai:doaj.org-article:4b94a6bf34874508a18178ee46cdecbb2021-11-25T18:40:02ZPharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease10.3390/ph141111871424-8247https://doaj.org/article/4b94a6bf34874508a18178ee46cdecbb2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1187https://doaj.org/toc/1424-8247Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer’s Disease (AD). MicroRNAs (miR-NAs) target the 3′UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the <i>NLRP3</i>-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aβ<sub>42</sub>) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1β and IL-18 expression, as well as IL-18, IL-1β and caspase-1 production, were significantly augmented (<i>p</i> < 0.05) in LPS+Aβ<sub>42</sub>-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (<i>p</i> < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aβ<sub>42</sub>-stimulated PBMCs of AD patients (<i>p</i> < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1β and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD.Francesca La RosaRoberta MancusoSimone AgostiniFederica PianconeIvana MarventanoMarina SaresellaAmbra HernisChiara FenoglioDaniela GalimbertiElio ScarpiniMario ClericiMDPI AGarticleAlzheimer’s diseaseD4TmiRNAsNLRP3 inflammasomeMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1187, p 1187 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease D4T miRNAs NLRP3 inflammasome Medicine R Pharmacy and materia medica RS1-441
spellingShingle	Alzheimer’s disease D4T miRNAs NLRP3 inflammasome Medicine R Pharmacy and materia medica RS1-441 Francesca La Rosa Roberta Mancuso Simone Agostini Federica Piancone Ivana Marventano Marina Saresella Ambra Hernis Chiara Fenoglio Daniela Galimberti Elio Scarpini Mario Clerici Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
description	Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer’s Disease (AD). MicroRNAs (miR-NAs) target the 3′UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the <i>NLRP3</i>-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aβ<sub>42</sub>) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1β and IL-18 expression, as well as IL-18, IL-1β and caspase-1 production, were significantly augmented (<i>p</i> < 0.05) in LPS+Aβ<sub>42</sub>-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (<i>p</i> < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aβ<sub>42</sub>-stimulated PBMCs of AD patients (<i>p</i> < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1β and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD.
format	article
author	Francesca La Rosa Roberta Mancuso Simone Agostini Federica Piancone Ivana Marventano Marina Saresella Ambra Hernis Chiara Fenoglio Daniela Galimberti Elio Scarpini Mario Clerici
author_facet	Francesca La Rosa Roberta Mancuso Simone Agostini Federica Piancone Ivana Marventano Marina Saresella Ambra Hernis Chiara Fenoglio Daniela Galimberti Elio Scarpini Mario Clerici
author_sort	Francesca La Rosa
title	Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
title_short	Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
title_full	Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
title_fullStr	Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
title_full_unstemmed	Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease
title_sort	pharmacological and epigenetic regulators of nlrp3 inflammasome activation in alzheimer’s disease
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4b94a6bf34874508a18178ee46cdecbb
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Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease

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