Abstract
Neuroinflammation is a landmark of neuroinflammatory and neurodegenerative diseases. Matrix metalloproteinase (MMP)-9, one member of MMPs, has been shown to contribute to the pathology of these brain diseases. Several experimental models have demonstrated that lipopolysaccharide (LPS) exerts a pathological role through Toll-like receptors (TLRs) in neuroinflammation and neurodegeneration. However, the mechanisms underlying LPS-induced MMP-9 expression in rat brain astrocytes (RBA-1) are not completely understood. Here, we applied pharmacological inhibitors and siRNA transfection to assess the levels of MMP-9 protein, mRNA, and promoter activity, as well as protein kinase phosphorylation in RBA-1 cells triggered by LPS. We found that LPS-induced expression of pro-form MMP-9 and cell migration were mediated through TLR4, proto-oncogene tyrosine-protein kinase (c-Src), proline-rich tyrosine kinase 2 (Pyk2), platelet-derived growth factor receptor (PDGFR), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), p38 mitogen-activated protein kinase (MAPK), and Jun amino-terminal kinase (JNK)1/2 signaling molecules in RBA-1 cells. In addition, LPS-stimulated binding of c-Jun to the MMP-9 promoter was confirmed by chromatin immunoprecipitation (ChIP) assay, which was blocked by pretreatment with c-Src inhibitor II, PF431396, AG1296, LY294002, Akt inhibitor VIII, p38 MAP kinase inhibitor VIII, SP600125, and tanshinone IIA. These results suggest that in RBA-1 cells, LPS activates a TLR4/c-Src/Pyk2/PDGFR/PI3K/Akt/p38 MAPK and JNK1/2 pathway, which in turn triggers activator protein 1 (AP-1) activation and ultimately induces MMP-9 expression and cell migration.
Highlights
Astrocytes are specialized glial cells that constitute nearly half of the number of brain cells
Our results demonstrated that LPS-induced Matrix metalloproteinase (MMP)-9 expression was mediated through toll-like receptor 4 (TLR4)/c-Src/proline-rich tyrosine kinase 2 (Pyk2)/platelet-derived growth factor receptor (PDGFR)/phosphoinositide 3-kinase (PI3K)/Akt/p38 mitogen-activated protein kinase (MAPK) and Jun amino-terminal kinase (JNK)1/2-dependent activation of activator protein 1 (AP-1) associated with cell migration in RBA-1 cells
Pretreatment with either LY294002 or Akt inhibitor VIII attenuated the LPS-enhanced cell migration (Figure 6E). These results suggest that LPS-induced matrix metalloproteinase-9 (MMP-9) expression is mediated through a TLR4/c-Src/Pyk2/PDGFR/PI3K/Akt pathway in RBA-1 cells
Summary
Astrocytes are specialized glial cells that constitute nearly half of the number of brain cells. They play many important roles, such as nourishing neurons, metabolism of neurons, and regulation of concentrations of ions, neurotransmitters, and pH in the extracellular space in the central nerve system. Astrocytes can promote the survival of neurons and other glia by releasing neurotrophic and gliotrophic factors [2]. In contrast, their character is like immune cells. Astrocytes play an important role in several neuroinflammatory and neurodegenerative processes
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