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

Frontiers in Immunology

Kemal Ugur Tufekci¹  Sermin Genc²  Kursad Genc²  Burak I. Arioz⁴  Ceren Perihan Gonul⁴  Emre Tarakcioglu⁴  Bora Tastan⁴ 

[1] Department of Healthcare Services, Vocational School of Health Services, Izmir Democracy University, Izmir, Turkey;Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey;Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey;Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey;

关键词: dimethyl fumarate (DMF);    microglia;    NLRP3 inflammasome;    lipopolysaccharide (LPS);    sickness behaviors;    pyroptosis;   

DOI  :  10.3389/fimmu.2021.737065

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown