Abstract
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.
Highlights
Neuroinflammation is a conserved response to all kinds of threats in the central nervous system (CNS) involving certain cell types like neurons, microglia, and astrocytes [1]
We found that Dimethyl fumarate (DMF) significantly decreased the amounts of IL-1b (Figure 1A) and IL-18 (Figure 1B), which were induced by LPS and adenosine 5’-triphosphate (ATP) treatment
We observed that DMF significantly reduced both pro-IL-1b (Figures 1E, F) and secreted mature IL-1b protein levels (Figures 1E, G) against NLR Family Pyrin Domain Containing Protein 3 (NLRP3) inflammasome activation
Summary
Neuroinflammation is a conserved response to all kinds of threats in the central nervous system (CNS) involving certain cell types like neurons, microglia, and astrocytes [1]. Microglia are activated at once, and a rapid response occurs against the dangerous stimuli [2]. Lipopolysaccharide (LPS) -induced sickness behavior is a condition which exhibits depression-like symptoms such as fatigue, cognitive impairment, and limited physical activity [3]. A previous study by Aubert et al showed that LPS is adequate for inducing sickness behavior in mice [4]. Numerous proinflammatory cytokines have been proven to be associated with sickness behavior; interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a) [5]. One important activated pathway is the NLR Family Pyrin Domain Containing Protein 3 (NLRP3) inflammasome during acute neuroinflammation [6]
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