[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
TASTAN, Bora ✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuroinflammation Group ; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Arioz, Burak I ✱; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Tufekci, Kemal Ugur; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Department of Healthcare Services, Vocational School of Health Services, Izmir Democracy University, Izmir, Turkey
Tarakcioglu, Emre; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Gonul, Ceren Perihan; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Genc, Kursad; Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey
Genc, Sermin; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice.
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu Dokuz Eylül Üniversitesi
Funding text :
The study was funded by The Scientific and Technological Research Council of Turkey (TUBITAK, Project No: 215Z473) and Dokuz Eylul University Department of Scientific Research Projects (DEU-BAP, Project No: 2017.KB.SAG.039).
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