Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis
Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis
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DOI：
10.1002/eji.201141548
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发表时间：
2012-02-01
影响因子：
5.4
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;Nouailles, Geraldine;Kaufmann, Stefan H. E.
结核分枝杆菌(MTB)作为结核病的标志，在活动性疾病中可引起肺部肉芽肿性病变和全身炎症反应。炎症的分子调控与炎性小体组装有关。我们在小鼠模型中确定了MTB触发炎症小体激活的程度，以及这对结核病严重程度的影响。MTB可刺激巨噬细胞释放成熟的IL-1β，而减毒牛分枝杆菌卡介苗则无此作用。结核杆菌特异性地激活NLRP3炎症体，这种倾向严格受结核分枝杆菌毒力相关的Rd1位点控制。然而，Nlrp3基因缺陷的小鼠控制了肺结核病，这一特征与NLRP3独立于感染肺产生IL-1β有关。我们的研究表明，MTB以ESX-1依赖的方式激活巨噬细胞中的NLRP3炎症体。然而，在结核病期间，MTB促进NLRP3和caspase-1依赖的IL-1β在招募到肺实质的髓系细胞中的释放，从而在实验模型中克服体内NLRP3缺陷。
As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1 beta in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1 beta in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1-independent IL-1 beta release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.