Abstract：
Streptococcus suis (S. suis) type 2 (SS2) is an important zoonotic pathogen causing severe neural infections in pigs and causes serious threat to public health. Inflammasome activation plays an important role in the host against microbial infection but the role of inflammasome activation in the blood-brain barrier (BBB) integrity during S. suis infection is rarely studied. This study investigated the mechanism by which S. suis-induced NLRP3 inflammasome activation led to BBB disruption. Our results showed that S. suis infection activated NLRP3 inflammasome in brain microvascular endothelial cells (BMECs) leading to the secretion of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokines (CCL-2 and CXCL-2) as well as the cleavage of Gasdermin D (GSDMD) which were significantly attenuated by inflammasome inhibitor MCC950. Furthermore, S. suis infection significantly downregulated expression of tight junctions (TJs) proteins and trans-endothelial electrical resistance (TEER) while NLRP3 inhibition rescued S. suis-induced degradation of TJs proteins and significantly reduced the number of S. suis crossing BBB in transwell infection model. Moreover, recombinant IL-1β exacerbated the reduction of TJs proteins in BMECs. In murine S. suis-infection model, MCC950 reduced the bacterial load and the excessive inflammatory response in mice brain. In addition, the integrity of the BBB was protected with increased TJ proteins expression and decreased pathological injury after the inhibition of NLRP3 inflammasome, indicating NLRP3 inflammasome plays a destructive role in meningitis induced by S. suis. Our study expands the understanding on the role of NLRP3 inflammasome in bacterial meningitis, which provide the valuable information for the development of anti-infective agents targeting NLRP3 to treat bacterial meningitis.
摘要：
猪链球菌（S.suis）2型（SS2）是一种重要的人畜共患病原体，可引起猪的严重神经感染，对公众健康造成严重威胁。炎症小体激活在宿主抵抗微生物感染中起重要作用，但很少研究炎症小体激活在猪链球菌感染期间血脑屏障（BBB）完整性中的作用。这项研究调查了猪链球菌诱导的NLRP3炎性体激活导致BBB破坏的机制。我们的结果表明，猪链球菌感染激活了脑微血管内皮细胞（BMECs）中的NLRP3炎性体，导致促炎细胞因子（IL-1β，IL-6和TNF-α）和趋化因子（CCL-2和CXCL-2）以及GasderminD（GSDMD）的裂解被炎症体抑制剂MCC950显着减弱。此外，猪链球菌感染显着下调了紧密连接（TJs）蛋白和跨内皮电阻（TEER）的表达，而NLRP3抑制挽救了猪链球菌诱导的TJs蛋白降解，并显着减少了跨BBB的猪链球菌数量。感染模型。此外，重组IL-1β加剧了BMECs中TJs蛋白的减少。在鼠猪链球菌感染模型中，MCC950降低了小鼠脑内的细菌负荷和过度的炎症反应。此外,在抑制NLRP3炎性体后，BBB的完整性受到TJ蛋白表达增加和病理损伤减少的保护，表明NLRP3炎性体在猪链球菌引起的脑膜炎中起破坏性作用。我们的研究扩展了对NLRP3炎性体在细菌性脑膜炎中的作用的理解，为开发针对NLRP3的抗感染药物治疗细菌性脑膜炎提供了有价值的信息。
