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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: Tastan, Bora, Arioz, Burak I., Tufekci, Kemal Ugur, Tarakcioglu, Emre, Gonul, Ceren Perihan, Genc, Kursad, Genc, Sermin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631454/
https://www.ncbi.nlm.nih.gov/pubmed/34858398
http://dx.doi.org/10.3389/fimmu.2021.737065
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author Tastan, Bora
Arioz, Burak I.
Tufekci, Kemal Ugur
Tarakcioglu, Emre
Gonul, Ceren Perihan
Genc, Kursad
Genc, Sermin
author_facet Tastan, Bora
Arioz, Burak I.
Tufekci, Kemal Ugur
Tarakcioglu, Emre
Gonul, Ceren Perihan
Genc, Kursad
Genc, Sermin
author_sort Tastan, Bora
collection PubMed
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.
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spelling pubmed-86314542021-12-01 Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice Tastan, Bora Arioz, Burak I. Tufekci, Kemal Ugur Tarakcioglu, Emre Gonul, Ceren Perihan Genc, Kursad Genc, Sermin Front Immunol Immunology 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. Frontiers Media S.A. 2021-11-10 /pmc/articles/PMC8631454/ /pubmed/34858398 http://dx.doi.org/10.3389/fimmu.2021.737065 Text en Copyright © 2021 Tastan, Arioz, Tufekci, Tarakcioglu, Gonul, Genc and Genc https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tastan, Bora
Arioz, Burak I.
Tufekci, Kemal Ugur
Tarakcioglu, Emre
Gonul, Ceren Perihan
Genc, Kursad
Genc, Sermin
Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice
title 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_short 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
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631454/
https://www.ncbi.nlm.nih.gov/pubmed/34858398
http://dx.doi.org/10.3389/fimmu.2021.737065
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