Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, Jilin, 130062, China.
The Second Hospital of Jilin University, Changchun, Jilin, 130021, China.
Immunol Cell Biol. 2022 Jul;100(6):440-452. doi: 10.1111/imcb.12550. Epub 2022 May 16.
Giardia lamblia is a zoonotic protozoan that causes the diarrheal illness giardiasis, with the highest prevalence reported in the tropics and subtropics. Giardia is currently the most frequently identified pathogen in waterborne outbreaks in the United States. Nucleotide oligomerization domain (NOD) 1 and NOD2, intracellular NOD-like receptors, recognize pathogens to induce proinflammatory and antimicrobial responses. However, the roles of NOD1 and NOD2 signaling in Giardia infection have not yet been investigated. In the present study, the activation of NOD1 and NOD2 signaling pathways and the production of proinflammatory cytokines, reactive oxygen species (ROS) and nitric oxide in mouse macrophages stimulated with G. lamblia or parasite excretory-secretory products (ESPs) were examined. The results showed that G. lamblia and ESPs activated NOD2 and its downstream adaptor protein kinase, Receptor-interacting protein 2 (Rip2), in mouse macrophages. Blocking NOD2-Rip2 signaling significantly reduced the production of ROS and subsequently decreased the phosphorylation of nuclear factor-κB p65 and extracellular signal-regulated kinase, which in turn inhibited the production of four proinflammatory cytokines, namely, interleukin (IL)-1β, IL-6, IL-12p40 and tumor necrosis factor-α. In summary, our results indicate that the NOD2-Rip2 signal, which is activated by G. lamblia, contributes to the production of proinflammatory cytokines and ROS in mouse macrophages.
蓝氏贾第鞭毛虫是一种引起腹泻病贾第虫病的动物源原生动物，其流行率在热带和亚热带地区最高。蓝氏贾第鞭毛虫目前是美国水源性暴发中最常被识别的病原体。核苷酸寡聚化结构域（NOD）1 和 NOD2 是细胞内的 NOD 样受体，可识别病原体以诱导促炎和抗菌反应。然而，NOD1 和 NOD2 信号通路在蓝氏贾第鞭毛虫感染中的作用尚未得到研究。在本研究中，研究了 NOD1 和 NOD2 信号通路的激活以及用蓝氏贾第鞭毛虫或寄生虫排泄分泌产物（ESPs）刺激的小鼠巨噬细胞中促炎细胞因子、活性氧（ROS）和一氧化氮的产生。结果表明，蓝氏贾第鞭毛虫和 ESPs 激活了小鼠巨噬细胞中的 NOD2 及其下游衔接蛋白激酶受体相互作用蛋白 2（Rip2）。阻断 NOD2-Rip2 信号显著降低了 ROS 的产生，随后降低了核因子-κB p65 和细胞外信号调节激酶的磷酸化，从而抑制了四种促炎细胞因子，即白细胞介素（IL）-1β、IL-6、IL-12p40 和肿瘤坏死因子-α的产生。总之，我们的结果表明，蓝氏贾第鞭毛虫激活的 NOD2-Rip2 信号有助于小鼠巨噬细胞中促炎细胞因子和 ROS 的产生。
