title: B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis.
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-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.
authors.affiliation: Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.|Pediatric Research Institute of Soochow University, Suzhou, China.
authors.forename: Xuqin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Blankson
authors.affiliation: Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.
authors.forename: Danping
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
authors.forename: H Paul
authors.initials: HP
authors.lastname: Redmond
authors.affiliation: Department of Neurology, Children's Hospital of Soochow University, Suzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
authors.forename: Jiang Huai
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Pediatric Research Institute of Soochow University, Suzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008586:Meningitis, Pneumococcal / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D060887:B7 Antigens; C486038:Cd276 protein, mouse; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases