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Meningitis is a major clinical manifestation of <i>Escherichia coli</i> (<i>E. coli</i>) infection characterized by inflammation of the meninges and subarachnoid space. Many chemokines are secreted during meningitic <i>E. coli</i> infection, of which C-X-C motif chemokine 3 (CXCL3) is the most highly expressed. However, it is unclear how CXCL3 plays a role in meningitic <i>E. coli</i> infection. Therefore, this study used in vitro and in vivo assays to clarify these contributions and to identify novel therapeutic targets for central nervous system inflammation. We found a significantly upregulated expression of CXCL3 in human brain microvascular endothelial cells and U251 cells after meningitic <i>E. coli</i> infection, and the CXCL3 receptor, C-X-C motif chemokine receptor 2 (CXCR2), was expressed in microglia. Furthermore, CXCL3 induced <i>M1</i> microglia by selectively activating mitogen-activated protein kinases signaling and significantly upregulating tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, nitric oxide synthase 2 (NOS2), and cluster of differentiation 86 (CD86) expression levels, promoting an inflammatory response. Our findings clarify the role of CXCL3 in meningitic <i>E. coli</i>-induced neuroinflammation and demonstrate that CXCL3 may be a potential therapeutic target for future investigation and prevention of <i>E. coli</i>-induced neuroinflammation.