School of Medical Laboratory, Tianjin Medical University, Tianjin, China.
Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China.
Front Immunol. 2021 Sep 16;12:747370. doi: 10.3389/fimmu.2021.747370. eCollection 2021.
() is a foodborne pathogen that causes severe diseases, such as endocarditis, sepsis, and bacteremia. As an important component of innate immune system, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in defense against pathogen infection. However, the cellular mechanism of NLRP3 inflammasome activation during infection remains unknown. In the present study, we found that spleen tyrosine kinase (Syk) and c-Jun N-terminal kinase (JNK) were rapidly phosphorylated during infection. Moreover, a Syk/JNK inhibitor and Syk/JNK siRNA not only reduced NLRP3 inflammasome-associated molecule expression at the protein and mRNA levels, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation, and interleukin-1β (IL-1β), and IL-18 release but also rescued the decreased NIMA-related kinase 7 (NEK7) expression level following suppression of the NEK7-NLRP3 interaction in macrophages. Interestingly, Syk/JNK phosphorylation levels and NLRP3 inflammasome-associated molecule expression were decreased by blockade of K efflux. Furthermore, activation of the NLRP3 inflammasome and a lower NEK7 protein level were found upon infection. Taken together, our data indicated that infection induces a K efflux/Syk/JNK/NEK7-NLRP3 signaling pathway and the subsequent activation of the NLRP3 inflammasome for the release of proinflammatory cytokines. This study expands our understanding of the basic molecular mechanism regulating inflammation and provides potential value for anti-infective drug development against infection.
李斯特菌是一种食源性致病菌，可引起心内膜炎、败血症和菌血症等严重疾病。作为先天免疫系统的重要组成部分，NLR 家族 pyrin 域包含 3（NLRP3）炎症小体在防御病原体感染中起着关键作用。然而，李斯特菌感染过程中 NLRP3 炎症小体的激活的细胞机制尚不清楚。在本研究中，我们发现脾脏酪氨酸激酶（Syk）和 c-Jun N 末端激酶（JNK）在李斯特菌感染过程中迅速磷酸化。此外，Syk/JNK 抑制剂和 Syk/JNK siRNA 不仅降低了 NLRP3 炎症小体相关分子在蛋白和 mRNA 水平的表达、凋亡相关斑点样蛋白（ASC）斑点形成以及白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的释放，还挽救了巨噬细胞中抑制 NEK7-NLRP3 相互作用后 NLRP3 炎症小体相关分子表达的降低。有趣的是，Syk/JNK 磷酸化水平和 NLRP3 炎症小体相关分子的表达通过阻止 K 外流而降低。此外，在李斯特菌感染时发现 NLRP3 炎症小体的激活和更低的 NEK7 蛋白水平。总之，我们的数据表明李斯特菌感染诱导 K 外流/Syk/JNK/NEK7-NLRP3 信号通路的激活，随后激活 NLRP3 炎症小体释放促炎细胞因子。本研究扩展了我们对调节炎症的基本分子机制的理解，并为针对李斯特菌感染的抗感染药物开发提供了潜在价值。
