The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release
The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release
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DOI：
10.4049/jimmunol.1100790
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发表时间：
2011-11-15
影响因子：
4.4
通讯作者：
Koedel, Uwe
中科院分区：
文献类型：
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作者：
Hoegen, Tobias;Tremel, Nadin;Koedel, Uwe
肺炎链球菌脑膜炎通过炎症相关途径引起脑损伤，其作用机制和身份尚不清楚。我们以前确定半胱天冬酶-1，激活前体IL-1型细胞因子，作为肺炎球菌脑膜炎炎症的中央介质。在这项研究中，我们证明，缺乏炎性小体成分ASC或NLRP 3，主要参与半胱天冬酶-1激活降低临床和组织学疾病的严重程度，以及在小鼠肺炎球菌脑膜炎的脑炎症评分。使用特异性抑制剂（阿那白滞素和rIL-18结合蛋白），我们进一步表明ASC和NLRP 3依赖性病理改变仅与IL-1 β和IL-18的分泌有关。此外，使用分化的人THP-1细胞，我们证明了肺炎球菌孔形成毒素肺炎球菌溶血素是肺炎球菌攻击后IL-1 β表达和炎性小体激活的关键诱导剂。后者依赖于ATP的释放、溶酶体失稳（但不是破坏）和组织蛋白酶B活化。该途径在体内的重要性得到了我们的观察结果的支持，即肺炎球菌溶血素和组织蛋白酶B抑制的缺乏与小鼠肺炎球菌脑膜炎的更好的临床过程和更少的脑炎症相关。总的来说，我们的研究表明NLRP 3炎性小体在肺炎球菌脑膜炎的病理学中起着核心作用。因此，干扰炎性小体激活可能是一个有前途的靶点，为这种疾病的持续治疗。免疫学杂志，2011，187：5440-5451。
Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18-binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1 beta and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1 beta expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease. The Journal of Immunology, 2011, 187: 5440-5451.