MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment
MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment
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DOI：
10.1172/jci67604
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Kaufmann, Stefan H. E.
中科院分区：
文献类型：
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作者：
Dorhoi, Anca;Iannaccone, Marco;Kaufmann, Stefan H. E.
在慢性感染和炎症过程中，如在结核病（TB）中，控制先天免疫细胞运输的分子机制尚未完全了解。在活动性TB期间，髓样细胞浸润肺并维持局部炎症。虽然协调这些过程的化学引诱物越来越多地被认识到，但决定其可用性的转录后事件尚不清楚。我们鉴定了microRNA-223（miR-223）作为结核病患者血液和肺实质中以及小鼠结核病期间上调的小非编码RNA。miR-223的缺失使TB抗性小鼠对急性肺部感染高度敏感。miR-223（-/-）小鼠的致死性显然不是由于抗分枝杆菌T细胞应答的缺陷。miR-223（-/-）动物中的TB加重可通过CXCL 2、CCL 3和IL-6的中和、中性粒细胞的mAb耗竭和Cxcr 2的基因缺失而部分逆转。我们发现，miR-223控制了骨髓细胞的肺募集，从而控制了嗜中性粒细胞驱动的致命炎症。我们得出结论，miR-223直接靶向骨髓细胞中的趋化因子CXCL 2、CCL 3和IL-6。我们的研究不仅揭示了单个miRNA在结核病中的重要作用，还确定了miR-223的新靶点并为其分配了生物学功能。通过化学引诱物调节白细胞趋化性，miR-223对于控制TB和潜在的其他慢性炎性疾病至关重要。
The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223(-/-) mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223(-/-) animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.