College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Int J Mol Sci. 2022 Oct 14;23(20):12257. doi: 10.3390/ijms232012257.
It has been established that kallikrein12 (KLK12) expression is closely related to bovine tuberculosis (bTB) development. Herein, we sought to clarify the regulatory mechanism of KLK12 and its application in tuberculosis diagnosis. KLK12 knockdown macrophages were produced by siRNA transfection. Bradykinin receptors (BR, including B1R and B2R) were blocked with specific inhibitors. Mannose-capped lipoarabinomannan (ManLAM) was extracted from () and used to study the mechanism of KLK12 activation. In addition, we constructed different mouse models representing the latent and active stages of infection. Mouse models and clinical serum samples were used to assess the diagnostic value of biomarkers. Through the above methods, we confirmed that KLK12 regulates MMP-1 and MMP-9 via BR. KLK12 upregulation is mediated by the -specific antigen ManLAM. KLK12, MMP-1, and MMP-9 harbor significant value as serological markers for differentiating between latent and active bTB, especially KLK12. In conclusion, we identified a novel signaling pathway, KLK12/BR/ERK/MMPs, in -infected macrophages, which is activated by ManLAM. From this signaling pathway, KLK12 can be used as a serological marker to differentiate between latent and active bTB. Importantly, KLK12 also has enormous potential for the clinical diagnosis of human tuberculosis (TB).
已经确定激肽释放酶 12（KLK12）的表达与牛结核病（bTB）的发展密切相关。在此，我们旨在阐明 KLK12 的调控机制及其在结核病诊断中的应用。通过 siRNA 转染产生 KLK12 敲低巨噬细胞。用特异性抑制剂阻断缓激肽受体（BR，包括 B1R 和 B2R）。从 （）中提取甘露糖封端的脂阿拉伯甘露聚糖（ManLAM），用于研究 KLK12 激活的机制。此外，我们构建了不同的小鼠模型，代表 感染的潜伏和活动期。使用小鼠模型和临床血清样本评估生物标志物的诊断价值。通过上述方法，我们证实 KLK12 通过 BR 调节 MMP-1 和 MMP-9。KLK12 的上调受特异性抗原 ManLAM 介导。KLK12、MMP-1 和 MMP-9 作为区分潜伏和活动性 bTB 的血清学标志物具有重要价值，尤其是 KLK12。总之，我们在受感染的巨噬细胞中鉴定了一种新的信号通路 KLK12/BR/ERK/MMPs，该信号通路被 ManLAM 激活。从这个信号通路中，KLK12 可以用作区分潜伏性和活动性 bTB 的血清学标志物。重要的是，KLK12 对人类结核病（TB）的临床诊断也具有巨大潜力。
