State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China.
Key Laboratory of Luminescent and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
J Cell Physiol. 2021 Nov;236(11):7405-7420. doi: 10.1002/jcp.30411. Epub 2021 May 7.
Tuberculosis caused by Mycobacterium tuberculosis remains a serious global public health threat. Macrophage polarization is crucial for the innate immunity against M. tuberculosis. However, how M. tuberculosis interferes with macrophage polarization is elusive. We demonstrated here that M. tuberculosis PPE36 (Rv2108) blocked macrophage M1 polarization, preventing the cytokine storm, and alleviating inflammatory damage to mouse immune organs. PPE36 inhibited the polarization of THP-1 cell differentiation to M1 macrophages, reduced mitochondrial dehydrogenase activity, inhibited the expression of CD16, and repressed the expression of pro-inflammatory cytokines IL-6 and TNF-α, as well as chemokines CXCL9, CXCL10, CCL3, and CCL5. Intriguingly, in the mouse infection model, PPE36 significantly alleviated the inflammatory damage of immune organs caused by a cytokine storm. Furthermore, we found that PPE36 inhibited the polarization of macrophages into mature M1 macrophages by suppressing the ERK signaling. The study provided novel insights into the function and mechanism of action of M. tuberculosis effector PPE36 both at the cellular and animal level.
结核分枝杆菌引起的结核病仍然是一个严重的全球公共卫生威胁。巨噬细胞极化对于针对结核分枝杆菌的先天免疫至关重要。然而，结核分枝杆菌如何干扰巨噬细胞极化仍然难以捉摸。我们在这里证明，结核分枝杆菌 PPE36（Rv2108）阻断了巨噬细胞 M1 极化，防止了细胞因子风暴，并减轻了对小鼠免疫器官的炎症损伤。PPE36 抑制了 THP-1 细胞向 M1 巨噬细胞分化的极化，降低了线粒体脱氢酶活性，抑制了 CD16 的表达，并抑制了促炎细胞因子 IL-6 和 TNF-α以及趋化因子 CXCL9、CXCL10、CCL3 和 CCL5 的表达。有趣的是，在小鼠感染模型中，PPE36 显著减轻了细胞因子风暴引起的免疫器官炎症损伤。此外，我们发现 PPE36 通过抑制 ERK 信号通路抑制巨噬细胞向成熟 M1 巨噬细胞的极化。该研究在细胞和动物水平上为结核分枝杆菌效应蛋白 PPE36 的功能和作用机制提供了新的见解。
