Abstract
BackgroundLipoteichoic acid (LTA) is a component of gram-positive bacterial cell walls and may be elevated in the cerebrospinal fluid of patients suffering from meningitis. Among matrix metalloproteinases (MMPs), MMP-9 has been observed in patients with brain inflammatory diseases and may contribute to the pathology of brain diseases. Moreover, several studies have suggested that increased oxidative stress is implicated in the pathogenesis of brain inflammation and injury. However, the molecular mechanisms underlying LTA-induced redox signal and MMP-9 expression in brain astrocytes remain unclear.ObjectiveHerein we explored whether LTA-induced MMP-9 expression was mediated through redox signals in rat brain astrocytes (RBA-1 cells).MethodsUpregulation of MMP-9 by LTA was evaluated by zymographic and RT-PCR analyses. Next, the MMP-9 regulatory pathways were investigated by pretreatment with pharmacological inhibitors or transfection with small interfering RNAs (siRNAs), Western blotting, and chromatin immunoprecipitation (ChIP)-PCR and promoter activity reporter assays. Moreover, we determined the cell functional changes by migration assay.ResultsThese results showed that LTA induced MMP-9 expression via a PKC(α)-dependent pathway. We further demonstrated that PKCα stimulated p47phox/NADPH oxidase 2 (Nox2)-dependent reactive oxygen species (ROS) generation and then activated the ATF2/AP-1 signals. The activated-ATF2 bound to the AP-1-binding site of MMP-9 promoter, and thereby turned on MMP-9 gene transcription. Additionally, the co-activator p300 also contributed to these responses. Functionally, LTA-induced MMP-9 expression enhanced astrocytic migration.ConclusionThese results demonstrated that in RBA-1 cells, activation of ATF2/AP-1 by the PKC(α)-mediated Nox(2)/ROS signals is essential for upregulation of MMP-9 and cell migration enhanced by LTA.
Highlights
Lipoteichoic acid (LTA) is a component of gram-positive bacterial cell walls and may be elevated in the cerebrospinal fluid of patients suffering from meningitis
We further demonstrated that PKCα stimulated p47phox/NADPH oxidase 2 (Nox2)-dependent reactive oxygen species (ROS) generation and activated the ATF2/AP-1 signals
To determine whether ROS participated in matrix metalloproteinases (MMPs)-9 induction, pretreatment of RBA-1 cells with N-acetylcysteine (NAC, a ROS scavenger, 10 mM) attenuated the LTA-induced MMP-9 protein and mRNA expression (Figure 1a and b), suggesting that ROS may play a crucial role in LTA-induced MMP-9 expression in RBA-1 cells
Summary
Lipoteichoic acid (LTA) is a component of gram-positive bacterial cell walls and may be elevated in the cerebrospinal fluid of patients suffering from meningitis. In the CNS, the glial cells such as astrocytes and microglia are regarded as targets in grampositive bacterial infection [9,10]. Lipoteichoic acid (LTA) is a major component of gram-positive bacterial cell walls that induces glial inflammatory activation in vitro and in vivo [11], mediated through TLR2 signaling [12]. TLR signaling has been shown to be involved in brain inflammatory responses [13], accompanied by upregulation of several genes with proinflammatory and proapoptotic capabilities [14]. The role of MMP9 in astrocytes, the major regulator of fundamental biological functions of the CNS [15], in LTA-induced brain inflammation remains poorly defined
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