Search

Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element pathway has been proved to be the key regulator in reducing inflammatory damage, which is involved in subarachnoid hemorrhage (SAH). Here, in a traditional in vitro SAH model, we investigated the effect of Nrf2 depletion on pro-inflammatory cytokines production. Primary cultured astrocytes from Nrf2 wild type (WT) or knockout (KO) mouse were exposed or not exposed to oxyhemoglobin (OxyHb). Then the DNA-binding activity of transcription factor nuclear factor-κB (NF-κB) was detected by EMSA. The expression of TNF-α, IL-1β, IL-6 and MMP9 were evaluated. The activity of MMP9 was measured by Gelatin zymography. After exposure to OxyHb, NF-κB was activated and the expression of downstream pro-inflammatory cytokines was up-regulated in astrocytes. And such up-regulation was much higher in KO astrocytes than in WT astrocytes, which means more aggravated inflammation in Nrf2 deficient astrocytes. These results suggest that astrocytes participate in inflammatory process after SAH and the absence of Nrf2 may induce more aggressive inflammation through activation of NF-κB pathway. [ABSTRACT FROM AUTHOR]

CLEC16A, C-type lectin domain family 16, member A was recently found to be associated with inflation process in the autoimmune diseases. In this study, we elucidated the dynamic expression changes and localization of CLEC16A in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CLEC16A expression was strongly induced in active astrocytes in inflamed cerebral cortex. In vitro studies indicated that the up-regulation of CLEC16A may be involved in the subsequent astrocyte activation following LPS challenge. And Knock-down of CLEC16A in cultured primary astrocytes by siRNA showed that CLEC16A was required for the activation of astrocytes induced by LPS. Collectively, these results suggested CLEC16A may be important in host defense in astrocyte-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammtion in CNS. [ABSTRACT FROM AUTHOR]

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens , has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1β in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway. Unlabelled Image • Matrine suppressed inflammation, demyelination and inflammatory cytokines in the CNS of EAE. • Matrine inhibited HMGB1, TLR4 expression in both astrocytes and microglia. • Matrine also inhibited MyD88, TRAF6 expression and NF-κB activation, with upregulated expression of IκB-α, an inhibitory molecule for NF-κB activation in the CNS. [ABSTRACT FROM AUTHOR]