Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice

NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the sympto...

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Autores principales:	Bora Tastan, Burak I. Arioz, Kemal Ugur Tufekci, Emre Tarakcioglu, Ceren Perihan Gonul, Kursad Genc, Sermin Genc
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	dimethyl fumarate (DMF) microglia NLRP3 inflammasome lipopolysaccharide (LPS) sickness behaviors pyroptosis Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/b60a1794759e426ca70953d604e6e91d
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spelling	oai:doaj.org-article:b60a1794759e426ca70953d604e6e91d2021-11-10T07:20:09ZDimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice1664-322410.3389/fimmu.2021.737065https://doaj.org/article/b60a1794759e426ca70953d604e6e91d2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.737065/fullhttps://doaj.org/toc/1664-3224NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo. For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF’s effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12–14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro. Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.Bora TastanBora TastanBurak I. AriozBurak I. AriozKemal Ugur TufekciKemal Ugur TufekciEmre TarakciogluEmre TarakciogluCeren Perihan GonulCeren Perihan GonulKursad GencSermin GencSermin GencFrontiers Media S.A.articledimethyl fumarate (DMF)microgliaNLRP3 inflammasomelipopolysaccharide (LPS)sickness behaviorspyroptosisImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	dimethyl fumarate (DMF) microglia NLRP3 inflammasome lipopolysaccharide (LPS) sickness behaviors pyroptosis Immunologic diseases. Allergy RC581-607
spellingShingle	dimethyl fumarate (DMF) microglia NLRP3 inflammasome lipopolysaccharide (LPS) sickness behaviors pyroptosis Immunologic diseases. Allergy RC581-607 Bora Tastan Bora Tastan Burak I. Arioz Burak I. Arioz Kemal Ugur Tufekci Kemal Ugur Tufekci Emre Tarakcioglu Emre Tarakcioglu Ceren Perihan Gonul Ceren Perihan Gonul Kursad Genc Sermin Genc Sermin Genc Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
description	NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo. For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF’s effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12–14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro. Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.
format	article
author	Bora Tastan Bora Tastan Burak I. Arioz Burak I. Arioz Kemal Ugur Tufekci Kemal Ugur Tufekci Emre Tarakcioglu Emre Tarakcioglu Ceren Perihan Gonul Ceren Perihan Gonul Kursad Genc Sermin Genc Sermin Genc
author_facet	Bora Tastan Bora Tastan Burak I. Arioz Burak I. Arioz Kemal Ugur Tufekci Kemal Ugur Tufekci Emre Tarakcioglu Emre Tarakcioglu Ceren Perihan Gonul Ceren Perihan Gonul Kursad Genc Sermin Genc Sermin Genc
author_sort	Bora Tastan
title	Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title_short	Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title_full	Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title_fullStr	Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title_full_unstemmed	Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title_sort	dimethyl fumarate alleviates nlrp3 inflammasome activation in microglia and sickness behavior in lps-challenged mice
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b60a1794759e426ca70953d604e6e91d
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Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice

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