Abstract
Streptococcus pneumoniae meningitis is an intractable disease of the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family and found to participate in the immune inflammatory response. In this study, we investigated if activation of the classical inflammatory signaling pathway, myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB), regulates BDNF expression in experimental S. pneumoniae meningitis. MyD88 knockout (myd88−/−) mice and wild-type littermates were infected intracisternally with S. pneumoniae suspension. Twenty-four hours after inoculation, histopathology of brains was evaluated. Cytokine and chemokine in brains and spleens was analyzed using ELISA. NF-κB activation was evaluated using EMSA. Cortical and hippocampal BDNF was assessed using RT-PCR and ELISA, respectively. BDNF promoter activity was evaluated using ChIP-PCR. myd88−/− mice showed an obviously weakened inflammatory host response. This diminished inflammation was consistent with worse clinical parameters, neuron injury, and apoptosis. Deficiency in MyD88 was associated with decreased BDNF expression. Furthermore, we identified a valid κB-binding site in the BDNF promoter, consistent with activation of NF-κB induced by inflammation. To sum up, MyD88/NF-κB signaling has a crucial role in up-regulating BDNF, which might provide potential therapeutic targets for S. pneumoniae meningitis.
Highlights
Streptococcus pneumoniae meningitis is an invasive and often intractable disease of the central nervous system (CNS)
The present results demonstrate that S. pneumoniae infection drives robust gene expression of cytokines and chemokines in the CNS and peripheral immune organs, along with Brain-derived neurotrophic factor (BDNF) gene and protein expression in the cortex and hippocampus
The activity of myeloid differentiation factor 88 (MyD88)/NF-κB signaling is crucial to innate immune response, but it is required for BDNF expression
Summary
Streptococcus pneumoniae meningitis is an invasive and often intractable disease of the central nervous system (CNS). Increasing evidence has demonstrated that activation of NF-κB can lead to uncontrolled expression of those pro-inflammatory mediators, which contributes to the pathogenesis of disease processes[7]. Dysfunction in the regulation of BDNF is associated with numerous disorders of CNS, including Alzheimer’s disease (AD), multiple sclerosis (MS), depression, and unacceptable outcomes of bacterial meningitis[14,15,16,17]. Administration of exogenous BDNF increased the neuronal population in both the cortex and hippocampus, and reversed brain damage[20]. These findings indicate that regulatory expression of BDNF may be a part of the host inflammatory response in S. pneumoniae meningitis. We aimed to investigate if activation of the classical inflammatory signaling pathway, namely the MyD88/NF-κB signaling pathway, regulates BDNF expression in experimental S. pneumoniae meningitis
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