Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 1, Pages 347-355Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1103715
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Funding
- National Natural Science Foundation of China [30972718, 30870808]
- Jiangsu Medical Key Discipline Grant [XK201120]
- Jiangsu Innovation Team Grant [LJ201141]
- Science Foundation Ireland [SFI/08/RFP/BIC1734]
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In addition to a well-documented role in regulating T cell-mediated immune responses, B7-H3, a newly discovered member of the B7 superfamily, has been recently identified as a costimulator in the innate immunity-mediated inflammatory response. In this study, we further report that B7-H3 participates in the development of pneumococcal meningitis in a murine model. Exogenous administration of B7-H3 strongly amplified the inflammatory response, exacerbated blood-brain barrier disruption, and aggravated the clinical disease status in Streptococcus pneumoniae-infected C3H/HeN wild-type mice. Consistent with the in vivo findings, B7-H3 substantially augmented proinflammatory cytokine and chemokine production, upregulated NF-kappa B p65 and MAPK p38 phosphorylation, and enhanced the nuclear transactivation of NF-kappa B p65 at both TNF-alpha and IL-6 promoters in S. pneumoniae-stimulated primary murine microglia cells. These B7-H3-associated in vitro and in vivo effects appeared to be dependent on TLR2 signaling, as B7-H3 almost completely lost its amplifying actions in both TLR2-deficient microglial cells and TLR2-deficient mice. Furthermore, administration of the anti-B7-H3 mAb (MIH35) attenuated the inflammatory response and ameliorated blood-brain barrier disruption in S. pneumoniae-infected wild-type mice. Collectively, our results indicate that B7-H3 plays a contributory role in the development of S. pneumoniae infection-induced bacterial meningitis. The Journal of Immunology, 2012, 189: 347-355.
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