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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Published Version
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
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Published Version
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