Abstract
BackgroundStreptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated.Methodsp75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed.ResultsOur results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokines/mediators (IL-1β, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis.ConclusionOur findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.
Highlights
Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders
Increased p75 neurotrophin receptor (p75NTR) expression 24 h after pneumococcal meningitis (PM) and is mainly expressed in astrocytes and neuron cells To investigate the role of Precursor brain-derived neurotrophic factor (proBDNF)/p75NTR in rats after PM, proBDNF and p75NTR protein expression in the cortex and hippocampus were examined by Western blot analysis
LM11A‐31 pretreatment mitigates the clinical and pathological severity of rats at 24 h after PM To determine whether the p75NTR signaling pathway participates in the PM pathogenesis, regulates p75NTR can directly affect the clinical and pathological severity post-infection, the rats were pretreated with a smallmolecule p75NTR signaling modulator, LM11A-31, once daily for 3 consecutive days prior to S. pneumoniae inoculation
Summary
Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Bacterial meningitis (BM) is a serious infection of the central nervous systems (CNS) with high morbidity and mortality worldwide. Pneumococcal meningitis (PM) causes long-term neurological defects than other BM pathogens, about 50% of the survivors have persistent neurological sequelae throughout their lives, including hearing impairment, learning, memory disorders and seizures [3]. During PM, S. pneumoniae invades the subarachnoid space with various virulence factors, and the brain-resident immune cells together with the recruited neutrophils produce a severe inflammatory response. The direct neurotoxicity produced by S. pneumoniae and the innate and adaptive inflammatory response caused by immunocompetent cells after recognition of bacteria together can severely PM-related central and peripheral nervous systems [4, 5]. We should strive to find alternative adjuvant therapies to reduce the burden of pediatric PM
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