B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis.
B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis.
复制标题
B7-H3 在实验性肺炎球菌脑膜炎期间通过放大 NF-κB p65 和 MAPK p38 激活增强炎症反应并加剧脑损伤
DOI：
10.1371/journal.pone.0171146
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Chen X;Li Y;Blankson S;Liu M;Huang D;Redmond HP;Huang J;Wang JH;Wang J
共刺激蛋白B7-H3通过TLR 2依赖性方式增强先天免疫相关的炎症反应，在实验性肺炎球菌脑膜炎的发生和进展中起促进作用。本研究的目的是阐明TLR 2介导的信号转导通路的组成部分，负责B7-H3增强炎症反应和随后的脑损伤在实验性肺炎球菌脑膜炎。给予B7-H3并不增加TLR 2和其他TLR 2上游组分的表达，但导致S.肺炎感染的小鼠。此外，B7-H3显著增强了S。肺炎诱导的S. pneumoniae脑中TLR 2下游NF-κB p65和MAPK p38通路的激活。肺炎感染的小鼠。值得注意的是，用特异性抑制剂阻断NF-κB p65和/或MAPK p38可显著减弱B7-H3放大的炎症反应，显著减少促炎细胞因子和趋化因子的产生，并显著改善B7-H3加重的血脑屏障破坏和疾病状态的严重程度。肺炎感染的小鼠。这些结果表明，靶向NF-κB p65和/或MAPK p38可能代表了一种有希望的治疗选择，用于改善肺炎球菌脑膜炎期间经常观察到的压倒性炎症反应相关的脑损伤。
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.