Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major.
Absence of Tumor Necrosis Factor Supports Alternative Activation of Macrophages in the Liver after Infection with Leishmania major.
复制标题
肿瘤坏死因子的缺乏支持肝脏巨噬细胞感染后巨噬细胞的替代激活。
DOI：
10.3389/fimmu.2018.00001
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Körner H
中科院分区：
文献类型：
--
作者：
Hu S;Marshall C;Darby J;Wei W;Lyons AB;Körner H
在正常耐药的C57BL/6J （B6.WT）小鼠中，肿瘤坏死因子（TNF）的缺失可引起利什曼原虫的致命感染。迄今为止，这种致命疾病的潜在致病机制仍然难以捉摸。我们找到了B6。缺乏tnf基因（B6.TNF−/−）的WT小鼠在接种L. major后不仅表现出皮肤损伤不愈合，而且表现出严重的肝脏感染。感染B6。TNF - / -小鼠肝脏肿大，炎症增加。此外，我们检测到积累的单核细胞来源的巨噬细胞群（CD45+F4/80+CD11bhiLy6Clow）显示出M2巨噬细胞表型，CD206、精氨酸酶-1和IL-6的高表达，支持IL-6可能参与M2分化的观点。在体外实验中，我们证明了IL-6上调M-CSF受体的表达，并扭曲单核细胞从树突状细胞向巨噬细胞的分化。这可以通过添加TNF来抵消。此外，TNF干扰il -6诱导的gp130信号转换器和转录激活器（STAT） 3和IL-4-STAT6信号的激活，从而消除il -6促进的M2巨噬细胞极化。因此，我们的研究结果支持了TNF在巨噬细胞炎症激活中的一般作用的概念，并定义了IL-6信号在TNF下游巨噬细胞极化中的新作用。
The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF−/−) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF−/− mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45+F4/80+CD11bhiLy6Clow) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF.