B7-H3 participates in the development of experimental pneumococcal meningitis by augmentation of the inflammatory response via a TLR2-dependent mechanism.
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-κB p65 and MAPK p38 phosphorylation, and enhanced the nuclear transactivation of NF-κB p65 at both TNF-α 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.
Department of Neurology, Affiliated Children's Hospital, Soochow University, Suzhou 215006, People's Republic of China.
Xuqin
X
Chen
Edel M
EM
Quinn
Hong
H
Ni
Jian
J
Wang
Siobhan
S
Blankson
H Paul
HP
Redmond
Jiang Huai
JH
Wang
Xing
X
Feng
D000818:Animals; D060887:B7 Antigens / Q000008:administration & dosage / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology*; D008586:Meningitis, Pneumococcal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011897:Random Allocation; D015398:Signal Transduction / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*
D060887:B7 Antigens; C486038:Cd276 protein, mouse; D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2