B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-[kappa]B p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis

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From: PLoS ONE(Vol. 12, Issue 1)
Publisher: Public Library of Science
Document Type: Report
Length: 6,688 words
Lexile Measure: 1790L

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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-[kappa]B p65 and MAPK p38 pathways in the brain of S. pneumoniae-infected mice. Notably, blockage of NF-[kappa]B 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 blood-brain barrier and severity of disease status in S. pneumoniae-infected mice. These results indicate that targeting NF-[kappa]B 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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Gale Document Number: GALE|A481039694