Department of Pathophysiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
J Cell Mol Med. 2019 Dec;23(12):7985-7998. doi: 10.1111/jcmm.14599. Epub 2019 Oct 9.
Non-tuberculous mycobacteria (NTM), also known as an environmental and atypical mycobacteria, can cause the chronic pulmonary infectious diseases. Macrophages have been suggested as the main host cell to initiate the innate immune responses to NTM infection. However, the molecular mechanism to regulate the antimicrobial immune responses to NTM is still largely unknown. Current study showed that the NTM clinical groups, Mycobacterium abscessus and Mycobacterium smegmatis, significantly induced the M1 macrophage polarization with the characteristic production of nitric oxide (NO) and marker gene expression of iNOS, IFNγ, TNF-α, IL1-β and IL-6. Interestingly, a non-histone nuclear protein, HMGN2 (high-mobility group N2), was found to be spontaneously induced during NTM-activated M1 macrophage polarization. Functional studies revealed that HMGN2 deficiency in NTM-infected macrophage promotes the expression of M1 markers and the production of NO via the enhanced activation of NF-κB and MAPK signalling. Further studies exhibited that HMGN2 knock-down also enhanced IFNγ-induced M1 macrophage polarization. Finally, we observed that silencing HMGN2 affected the survival of NTM in macrophage, which might largely relevant to enhanced macrophage polarization into M1 phenotype under the NTM infection. Collectively, current studies thus suggested a novel function of HMGN2 in regulating the anti-non-tuberculous mycobacteria innate immunity of macrophage.
非结核分枝杆菌（NTM），也被称为环境和非典型分枝杆菌，可引起慢性肺部感染性疾病。巨噬细胞被认为是启动对 NTM 感染固有免疫反应的主要宿主细胞。然而，调节抗 NTM 抗菌免疫反应的分子机制在很大程度上仍不清楚。本研究表明，NTM 临床株，脓肿分枝杆菌和耻垢分枝杆菌，显著诱导 M1 巨噬细胞极化，特征性地产生一氧化氮（NO）和 iNOS、IFNγ、TNF-α、IL1-β 和 IL-6 的标记基因表达。有趣的是，一种非组蛋白核蛋白，HMGN2（高迁移率族蛋白 N2），在 NTM 激活的 M1 巨噬细胞极化过程中被自发诱导。功能研究表明，在 NTM 感染的巨噬细胞中，HMGN2 缺乏会通过增强 NF-κB 和 MAPK 信号通路的激活来促进 M1 标记物的表达和 NO 的产生。进一步的研究表明，HMGN2 敲低也增强了 IFNγ诱导的 M1 巨噬细胞极化。最后，我们观察到沉默 HMGN2 影响 NTM 在巨噬细胞中的存活，这可能与 NTM 感染下巨噬细胞向 M1 表型极化增强有很大关系。总之，本研究提示 HMGN2 在调节巨噬细胞抗非结核分枝杆菌固有免疫方面具有新的功能。
