B7-H3 Participates in the Development of Experimental Pneumococcal Meningitis by Augmentation of the Inflammatory Response via a TLR2-Dependent Mechanism

Abstract

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.

B7 homolog 3 aggravates brain injury in a murine model of Streptococcus pneumoniae-induced meningitis

“…In the results of the present study, the reduction of NSE expression in the brain tissues of the mice treated with SP plus B7-H3 may reflect the following: i) NSE is primarily localized in the cytoplasm of neurons (10) and is not secreted; thus, an increase in its levels in the CSF or blood indicates structural damage of neuronal cells (8); ii) The number of existing functional neurons in the brain tissues that are available to be stained as NSE-positive by immunohistochemical analysis is markedly decreased due to apoptosis or necrosis caused by multiple factors exerting injurious effects, including exacerbated inflammation in (5), oxidative stress, lipid peroxidation, mitochondrial damage and BBB breakdown (1). Further reductions in NSE expression in brain tissues in response to combined SP and B7-H3 challenge indicate a greater degree of neuronal loss and structural neuronal damage, which is consistent with our previous study where it was identified that B7-H3 exacerbated the SP infection-induced proinflammatory response and BBB disruption (6). S100B belongs to the multi-genic family of Ca 2+ -binding proteins and is abundant in astrocytes, where it is found diffusely in the cytoplasm and is associated with membranes and cytoskeleton constituents (12).…”

“…Our previous study (5) found an abnormally high expression level of soluble B7-H3 (sB7H3) protein in children with bacterial meningitis. In a murine model of SP-induced meningitis, we also demonstrated that B7-H3 further augmented the inflammatory response, exacerbated BBB disruption, and aggravated the pathological injury associated with the disease (6). In order to investigate the impact of B7-H3 on brain damage during SP-induced meningitis, the present study examined the effect of B7-H3 on neuronal necrosis and apoptosis and the protein expression of NSE and S100B in brain tissues in a murine model of SP-induced meningitis.…”

“…Our previous study (6) demonstrated that B7-H3 participates in the development of SP infection-induced bacterial meningitis by amplifying the inflammatory response and exacerbating BBB disruption through a TLR2-dependent mechanism. Consistent with the above findings, the present study demonstrates that the administration of B7-H3 leads to increased cell apoptosis, upregulated S100B expression and downregulated NSE expression in brain tissues, which are probably associated with the ongoing loss of neurons.…”

“…SP is recognized by antigen-presenting cells binding to Toll-like receptor 2 (TLR2), one of the main pattern recognition receptors that lead to the activation of NF-κB (6,24) contributing to the transcription of numerous genes involved in the pathogenesis of SP meningitis, such as tumor necrosis factor-α, interleukin-1β (6), inducible nitric oxide synthase, and intercellular adhesion molecules (25,26). Our previous study (6) demonstrated that B7-H3 participates in the development of SP infection-induced bacterial meningitis by amplifying the inflammatory response and exacerbating BBB disruption through a TLR2-dependent mechanism.…”

Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy

“…A co-stimulatory role of B7-H3 on human T cells was initially reported in vitro (3). Murine studies showing B7-H3 worsens experimental autoimmune encephalomyelitis (EAE), arthritis, bacterial meningitis and chronic allograft rejection (13–15) supported this claim. However, subsequent studies have mostly shown that B7-H3 acts as a T cell co-inhibitor.…”