Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics
Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics
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DOI：
10.1002/eji.201344219
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发表时间：
2014-08-01
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;Yeremeev, Vladimir;Kaufmann, Stefan H. E.
最近在结核（TB）患者中发现了一种独特的IFN基因表达特征后，人们对IFN I型在结核分枝杆菌（Mtb）感染中的生物学功能的普遍兴趣增加了。在这里，我们证明缺乏IFN I受体（IFNAR1）的结核病易感小鼠在空气源性结核分枝杆菌感染后免于死亡。利用该实验模型模拟原发性进行性肺结核，我们分析了IFN i对免疫过程的影响。IFNAR1信号不影响t细胞反应，但显著改变炎症单核细胞和中性粒细胞向肺的迁移。这一过程是由IFNAR1在免疫细胞和组织驻留的耐辐射细胞上表达的。ifnar1驱动的结核易感性是由结核分枝杆菌复制增强和原位死亡事件，以及CXCL5/ cxcl1驱动的肺泡中性粒细胞积聚，随后结核分枝杆菌在肺吞噬细胞中离散区隔化启动的。早期中性粒细胞耗竭使结核病易感小鼠恢复到缺乏IFNAR1小鼠的水平。我们得出结论，IFN I改变了Mtb侵袭部位的早期先天事件，导致致命的免疫病理。这些数据为IFN I在肺结核中的有害作用提供了机制解释，并为理解IFN I在慢性炎症中的复杂作用奠定了基础。
General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation.