Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
Institute of Neuroscience, The First People's Hospital of Lianyungang, Lianyungang, China.
Virulence. 2022 Dec;13(1):1486-1501. doi: 10.1080/21505594.2022.2116169.
, an important food-borne pathogen, induces serious invasive infections and inflammation. The pro-inflammatory IL-1β functions against pathogenic infections and is elevated in various infection cases. However, the molecular mechanism of -mediated IL-1β secretion remains unknown. In this study, mouse macrophages (PMs) were used to establish infection model and multiple strategies were utilized to explore the mechanism of IL-1β secretion. IL-1β was elevated in infected murine serum, PMs lysates or supernatants. This process triggered NLRP3 levels upregulation, ASC oligomerization, as well as dot gathering of NLRP3 and speck-like signals of ASC in the cytoplasm. MCC950 blocked mediated IL-1β release. Meanwhile, NLRP3 inflammasome mediated the release of IL-1β in dose- and time-dependent manners, and the release of IL-1β was dependent on active caspase-1, as well as NLRP3 inflammasome was activated by potassium efflux and cathepsin B release ways. also enhanced TLR2 levels, and deletion of TLR2 obviously decreased IL-1β secretion. What's more, resulted in NF-κB p65 nuclear translocation partly in a TLR2-dependent manner. Blocking NF-κB using BAY 11-7082 almost completely inhibited NLRP3 inflammasome first signal pro-IL-1β expression. Blocking TLR2, NF-κB, NLRP3 inflammasome significantly downregulated IL-1β release and TNF-α and IL-6 levels. These data illustrate that caused IL-1β secretion in PMs is controlled by NLRP3 inflammasome, of which is mediated by NF-κB pathway and is partially dependent on TLR2, providing basis for drugs against .
志贺毒素（）是一种重要的食源性致病菌，可引发严重的侵袭性感染和炎症。促炎细胞因子白细胞介素-1β（IL-1β）在抵抗病原体感染方面发挥着重要作用，在各种感染病例中都会升高。然而，志贺毒素诱导的 IL-1β分泌的分子机制尚不清楚。在本研究中，我们使用小鼠巨噬细胞（PMs）建立了感染模型，并采用多种策略来探讨 IL-1β分泌的机制。结果显示，志贺毒素感染的小鼠血清、PMs 裂解物或上清液中 IL-1β水平升高。该过程触发了 NLRP3 水平的上调、ASC 寡聚化以及 NLRP3 和 ASC 斑点样信号在细胞质中的聚集。MCC950 阻断了志贺毒素介导的 IL-1β释放。同时，NLRP3 炎性小体以剂量和时间依赖的方式介导了 IL-1β的释放，并且 IL-1β的释放依赖于活性半胱天冬酶-1，NLRP3 炎性小体通过钾离子外流和组织蛋白酶 B 释放途径被激活。志贺毒素还增强了 TLR2 的水平，并且 TLR2 的缺失明显降低了 IL-1β的分泌。此外，志贺毒素导致 NF-κB p65 核转位部分依赖于 TLR2。使用 BAY 11-7082 阻断 NF-κB 几乎完全抑制了 NLRP3 炎性小体前体 IL-1β的表达。阻断 TLR2、NF-κB、NLRP3 炎性小体显著下调了 IL-1β、TNF-α 和 IL-6 的释放。这些数据表明，志贺毒素诱导 PMs 中 IL-1β的分泌是由 NLRP3 炎性小体控制的，该过程由 NF-κB 通路介导，并部分依赖于 TLR2，为针对的药物研发提供了依据。
