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

• Published in: PloS one 2017-01, Vol.12 (1), p.e0171146-e0171146
• Main Authors: Chen, Xuqin, Li, Yan, Blankson, Siobhan, Liu, Min, Huang, Danping, Redmond, H Paul, Huang, Jing, Wang, Jiang Huai, Wang, Jian
• Format: Article
• Language: English
• Subjects: Activation; Animals; Augmentation; B7 antigen; B7 Antigens - metabolism; Bacteria; Biology and Life Sciences; Blockage; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - microbiology; Blood-Brain Barrier - pathology; Brain - metabolism; Brain - microbiology; Brain - pathology; Brain damage; Brain Injuries - pathology; Brain injury; Brain research; Chemokines; Cytokines; Dendritic cells; Disease Progression; Enzyme Activation; Head injuries; Immunity; Inflammation; Inflammation - complications; Inflammation - metabolism; Inflammation - pathology; Inflammatory response; Innate immunity; Interleukin-1 Receptor-Associated Kinases - metabolism; Kinases; Lipoproteins; Male; MAP kinase; Medicine and Health Sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Meningitis; Meningitis, Pneumococcal - metabolism; Meningitis, Pneumococcal - microbiology; Meningitis, Pneumococcal - pathology; Mice; Mice, Inbred BALB C; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Neurology; NF-κB protein; p38 Mitogen-Activated Protein Kinases - metabolism; Pathogens; Pediatrics; Phosphorylation; Proteins; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - metabolism; Research and Analysis Methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Signal Transduction; Streptococcal Infections - enzymology; Streptococcal Infections - microbiology; Streptococcal Infections - pathology; Streptococcus infections; Streptococcus pneumoniae; Streptococcus pneumoniae - physiology; Surgery; TLR2 protein; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Transcription Factor RelA - metabolism; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171146

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 blood-brain 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.