IFNγ receptor down-regulation facilitates Legionella survival in alveolar macrophages.
IFNγ receptor down-regulation facilitates Legionella survival in alveolar macrophages.
复制标题
DOI：
10.1002/jlb.4ma1019-152r
复制
发表时间：
2020-02
影响因子：
5.5
通讯作者：
Hartland EL
中科院分区：
文献类型：
--
作者：
Yang C;McDermot DS;Pasricha S;Brown AS;Bedoui S;Lenz LL;van Driel IR;Hartland EL
嗜肺军团菌是一种机会性人类病原体，也是被称为军团病的急性肺炎的病原体。吸入后，细菌在肺泡巨噬细胞（AM）中复制，在称为含军团菌空泡的细胞内空泡内。我们最近发现，在体内，干扰素γ（IFNγ）是最佳清除细胞内L。单核细胞衍生的细胞（MC），但细胞因子似乎没有影响AM的清除。在这里，我们报告说，在L。在嗜肺军团菌肺部感染中，IFNγ受体亚单位1（IFNGR 1）在AM和中性粒细胞中表达下调，但在MC中没有，这为AM不能有效地限制L. pneumophila体内复制。为了验证这一点，我们使用了在AM中组成型表达IFNGR 1的小鼠，发现阻止IFNGR 1下调增强了AM限制L。嗜肺菌细胞内复制。IFNGR 1的下调不依赖于L. pneumophila表明细菌效应蛋白没有参与。与以前的工作相反，我们发现通过I型干扰素受体的信号传导不是巨噬细胞中IFNGR 1下调所必需的，而是MyD 88或Trif介导的NF-κB激活所必需的。这项工作揭示了在细菌感染期间负责巨噬细胞中IFNGR 1下调的替代信号通路。肺军团菌感染后NF-κB活化导致肺泡巨噬细胞IFNGR 1表达下调，有助于细胞内细菌存活。
Legionella pneumophila is an opportunistic human pathogen and causative agent of the acute pneumonia known as Legionnaire’s Disease. Upon inhalation, the bacteria replicate in alveolar macrophages (AM), within an intracellular vacuole termed the Legionella containing vacuole. We recently found that, in vivo, interferon γ (IFNγ) was required for optimal clearance of intracellular L. pneumophila by monocyte-derived cells (MC), but the cytokine did not appear to influence clearance by AM. Here, we report that during L. pneumophila lung infection, expression of the IFNγ receptor subunit 1 (IFNGR1) is downregulated in AM and neutrophils, but not MC, offering a possible explanation for why AM are unable to effectively restrict L. pneumophila replication in vivo. To test this, we used mice that constitutively express IFNGR1 in AM and found that prevention of IFNGR1 downregulation enhanced the ability of AM to restrict L. pneumophila intracellular replication. IFNGR1 downregulation was independent of the type IV Dot/Icm secretion system of L. pneumophila indicating that bacterial effector proteins were not involved. In contrast to previous work, we found that signalling via type I interferon receptors was not required for IFNGR1 downregulation in macrophages but rather that MyD88- or Trif- mediated NF-κB activation was required. This work has uncovered an alternative signalling pathway responsible for IFNGR1 downregulation in macrophages during bacterial infection. NF-κB activation following Legionella lung infection resulted in downregulation of IFNGR1 expression in alveolar macrophages contributing to intracellular bacterial survival.