Lithium ameliorates lipopolysaccharide-induced microglial activation via inhibition of toll-like receptor 4 expression by activating the PI3K/Akt/FoxO1 pathway

Abstract

BackgroundLithium, an effective mood stabilizer for the treatment of bipolar disorders, has been recently suggested to have a role in neuroprotection during neurodegenerative diseases. The pathogenesis of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus, in this study, we aimed to understand the role of lithium in microglial activation and to elucidate the underlying mechanism(s).MethodsPrimary microglial cells were pretreated with lithium and stimulated with lipopolysaccharide (LPS). The cells were assessed regarding the responses of pro-inflammatory cytokines, and the associated signaling pathways were evaluated.ResultsLithium significantly inhibited LPS-induced microglial activation and pro-inflammatory cytokine production. Further analysis showed that lithium could activate PI3K/Akt signaling. Analyses of the associated signaling pathways demonstrated that the lithium pretreatment led to the suppression of LPS-induced toll-like receptor 4 (TLR4) expressions via the PI3K/Akt/FoxO1 pathway.ConclusionsThis study demonstrates that lithium can inhibit LPS-induced TLR4 expression and microglial activation through the PI3K/Akt/FoxO1 signaling pathway. These results suggest that lithium plays an important role in microglial activation and neuroinflammation-related diseases, which may lead to a new therapeutic strategy for the treatment of neuroinflammation-related disorders.

Enhancement of LPS-Induced Microglial Inflammation Response via TLR4 Under High Glucose Conditions

“…It has been shown that inhibiting TLR4 expression can suppress LPS-stimulated production of IL-β and TNF-α in the BV-2 microglia cell line [22]. Our previous study showed that pre-treatment with lithium inhibits LPS-induced TLR4 expression and microglial activation through the PI3K/Akt/FoxO1 signaling pathway, which is in accordance with the results in this study [15]. We found that co-incubation with glucose and LPS increased the expression of TLR4 (Fig.…”

“…It is known that the JAK2/STAT3 pathway plays a role in regulating the expression of TLR4 in macrophages [16]. Our previous study demonstrated that TLR4 can regulate microglia activation and inflammatory response [15]. Thus, we next tested the hypothesis that high glucose could accelerate LPS-induced microglia inflammation via the JAK2/STAT3 pathway.…”

“…Primary microglia cells were cultured according to a previously described protocol with slight modification [15]. In brief, after decapitation, cerebral hemispheres of newborn Sprague Dawley (SD) rats were dissociated mechanically.…”

MCP-1 stimulates spinal microglia via PI3K/Akt pathway in bone cancer pain

“…For example, blockage of PI3K by its inhibitor LY294002 has been found to suppress tetrachlorodibenzo-pdioxin (TCDD) -enhanced proliferation of HAPI microglial cells (Xu et al, 2014). FoxO1, a member of the forkhead transcription factor family (FoxO), has been found to be a modulator in microglial activation induced by PI3K/Akt (Dong et al, 2014), and further, Akt activation has been found to precede NF-κB activation in inflammatory responses of activated microglia, which shows that Akt was upstream of NF-κB (Saponaro et al, 2012).…”

Lithium Ameliorates LPS-Induced Astrocytes Activation Partly via Inhibition of Toll-Like Receptor 4 Expression

“…It has been shown that inhibiting TLR4 expression can suppress LPS-stimulated production of IL-β and TNF-α in the BV-2 microglia cell line [35]. Our previous studies have confirmed the role of TLR4 in microglia activation clearly [26,36], but the precise effect of TLR4 on astrocytes activation remains to be elucidated. Recent data has showed that after TLR4 activation, astrocytes may cause alterations on the blood brain barrier (BBB), promote inflammation, and modulate immune responses [14].…”