B7-H3 augments inflammatory responses and exacerbates brain damage via amplifying NF-κB p65 and MAPK p38 activation during experimental pneumococcal meningitis
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Date
2017-01-31
Authors
Chen, Xuqin
Li, Yan
Blankson, Siobhan
Liu, Min
Huang, Danping
Redmond, H. Paul
Huang, Jing
Wang, Jiang Huai
Wang, Jian
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Publisher
Public Library of Science
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Abstract
The costimulatory protein B7-H3 has been shown to play a contributory role in the development and progression of experimental pneumococcal meningitis by augmentation of the innate immunity-associated inflammatory response via a TLR2-dependent manner. This study aimed to clarify the component(s) of TLR2-mediated signal transduction pathways responsible for B7-H3-augmented inflammatory response and subsequent brain damage during experimental pneumococcal meningitis. Administration of B7-H3 did not augment expression of TLR2 and other TLR2 upstream components, but led to an enhanced formation of MyD88-IRAK immunocomplex in the brain of S. pneumoniae-infected mice. Furthermore, B7-H3 substantially augmented S. pneumoniae-induced activation of TLR2 downstream NF-κB p65 and MAPK p38 pathways in the brain of S. pneumoniae-infected mice. Notably, blockage of NF-κB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified inflammatory response with significantly reduced proinflammatory cytokine and chemokine production, and markedly ameliorated B7-H3-exacerbated disruption of bloodbrain barrier and severity of disease status in S. pneumoniae-infected mice. These results indicate that targeting NF-κB p65 and/or MAPK p38 may represent a promising therapeutic option for amelioration of overwhelming inflammatory response-associated brain injury frequently observed during pneumococcal meningitis.
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Keywords
Pneumococcal , Meningitis , Inflammatory response
Citation
Chen X., Li Y., Blankson S., Liu M., Huang D., Redmond H.P., Huang, J., Wang, J.H. and Wang, J. (2017) ‘B7-H3 augments inflammatory responses and exacerbates brain damage via amplifying NF-κB p65 and MAPK p38 activation during experimental pneumococcal meningitis’, PLoS ONE 12(1), e0171146 (16pp). doi:10.1371/journal.pone.0171146