Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
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DOI：
10.1371/journal.ppat.1006367
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发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Elkington PT
中科院分区：
文献类型：
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作者：
Brace PT;Tezera LB;Bielecka MK;Mellows T;Garay D;Tian S;Rand L;Green J;Jogai S;Steele AJ;Millar TM;Sanchez-Elsner T;Friedland JS;Proud CG;Elkington PT
结核病仍然是一种全球性流行病，并推动肺基质破坏传播。虽然巨噬细胞中驱动炎症反应的途径已被相对较好地描述，但负调控途径的定义尚不明确。我们假设结核分枝杆菌（Mtb）特异性靶向负调控途径，以增强免疫病理学。通过PI 3 K/AKT/mTORC 1途径抑制信号传导增加了基质金属蛋白酶-1（MMP-1）基因表达和分泌，这是一种对TB发病机制至关重要的胶原酶，以及多种促炎细胞因子。在确诊的肺结核患者中，肉芽肿内不存在PI 3 K δ表达。Mtb感染抑制巨噬细胞PI 3 K δ基因表达。有趣的是，抑制促炎性p38和ERK MAPK下游的MNK途径也增加MMP-1分泌，同时抑制TH 1细胞因子的分泌。在eIF 4 E磷酸化水平证明了PI 3 K和MNK途径之间的串扰。Mtb全面抑制巨噬细胞中的MMP抑制途径，通过上调miRNA降低编码PI 3 K δ、mTORC-1和MNK-1的mRNA水平。因此，Mtb在巨噬细胞中破坏多个水平的负调控途径，以驱动促进传播的组织破坏性表型。结核分枝杆菌（Mtb）逃避宿主免疫的机制已得到充分描述，但Mtb还必须参与宿主免疫反应，以驱动组织破坏，空化和传播，作为其生命周期的一部分。我们确定了负调控途径，抑制致病性基质金属蛋白酶-1在原代人巨噬细胞的表达，包括以前未确定的作用MAP激酶相互作用激酶（MNK）途径抑制蛋白酶分泌。此外，这些途径在培养证实的肺结核患者的肉芽肿和体外感染的巨噬细胞中受到抑制。编码负调控分子的mRNA的稳定性降低，并且Mtb上调预测靶向其3 'UTR的多种microRNA。总之，这些发现表明，结核分枝杆菌通过破坏负调控途径使巨噬细胞表型偏向组织破坏。
Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission. The mechanisms whereby Mycobacterium tuberculosis (Mtb) evades host immunity are well described, but Mtb must also engage the host immune response to drive tissue destruction, cavitation and transmission as part of its life cycle. We identify negative regulatory pathways that suppress pathogenic matrix metalloproteinase-1 expression in primary human macrophages, including a previously unidentified role of the MAP kinase-interacting kinase (MNK) pathway in inhibiting protease secretion. Furthermore, these pathways are suppressed in granulomas of patients with culture-proven pulmonary tuberculosis and in infected macrophages in vitro. Stability of mRNA encoding negative regulatory molecules is reduced, and Mtb upregulates multiple microRNAs predicted to target their 3’UTR. Together, these findings demonstrate that Mtb skews the macrophage phenotype towards tissue destruction by disrupting negative regulatory pathways.