Dai Hui, Xu Dong, Su Jing, Jang Jingyuan, Chen Yingyu
Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, China.
1] Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, China [2] Center for Human Disease Genomics, Peking University, Beijing, China.
Sci Rep. 2015 Jul 28;5:12461. doi: 10.1038/srep12461.
The M1 and M2 states of macrophage are the two extremes of a physiologic/phenotypic continuum that is dynamically influenced by environmental signals. Molecular mechanism analysis indicated that they gain M1 and M2-related functions after encountering specific ligands in the tissue environment. Here, we first characterized the previously unknown immunobiological functions of mouse Tmem106a. This protein is abundantly expressed on the surface of mouse macrophages. Activation of Tmem106a by stimulation with anti-Tmem106a upregulated the expression of CD80, CD86, CD69 and MHC II on macrophage, and induced the release of TNF-α, IL-1β, IL-6, CCL2 and NO, but not IL-10. These effects were largely abrogated by pretreatment with siRNA against Tmem106a. Notably, anti-Tmem106a significantly increased iNOS production and phosphorylation of STAT1, and had no effect on the ARGINASE-1 or p-STAT6 level, indicating that anti-Tmem106a activated macrophages and polarized them into M1-like macrophages. Further analysis found that anti-Tmem106a stimulation increased phosphorylation of ERK-1/2, JNK, p38 MAPK, NF-κB p65 and IKKα/β, and promoted nuclear translocation of the cytosolic NF-κB p65 subunit. Collectively, these data suggest that mouse Tmem106a might be a new trigger of macrophage activation and have some influence toward the M1 state through the activation of the MAPKs and NF-κB pathway.
巨噬细胞的M1和M2状态是生理/表型连续统一体的两个极端，受到环境信号的动态影响。分子机制分析表明，它们在组织环境中遇到特定配体后获得M1和M2相关功能。在此，我们首先表征了小鼠Tmem106a此前未知的免疫生物学功能。该蛋白在小鼠巨噬细胞表面大量表达。用抗Tmem106a刺激激活Tmem106a可上调巨噬细胞上CD80、CD86、CD69和MHC II的表达，并诱导TNF-α、IL-1β、IL-6、CCL2和NO的释放，但不诱导IL-10的释放。针对Tmem106a的siRNA预处理可在很大程度上消除这些作用。值得注意的是，抗Tmem106a显著增加iNOS的产生和STAT1的磷酸化，而对精氨酸酶-1或p-STAT6水平没有影响，这表明抗Tmem106a激活巨噬细胞并将其极化为M1样巨噬细胞。进一步分析发现，抗Tmem106a刺激增加了ERK-1/2、JNK、p38 MAPK、NF-κB p65和IKKα/β的磷酸化，并促进了细胞质NF-κB p65亚基的核转位。总体而言，这些数据表明小鼠Tmem106a可能是巨噬细胞激活的新触发因素，并通过激活MAPKs和NF-κB途径对M1状态产生一定影响。
