The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation
The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation
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DOI：
10.4049/jimmunol.178.12.8022
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Nunez, Gabriel
中科院分区：
文献类型：
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作者：
Lamkanfi, Mohamed;Amer, Amal;Nunez, Gabriel
与Ipaf和半胱天冬酶-1类似，Nod样受体蛋白Naip 5限制嗜肺军团菌的细胞内增殖，嗜肺军团菌是一种称为军团病的严重肺炎的病原体。因此，Naip 5已被认为通过激活半胱天冬酶-1来调节巨噬细胞内的军团菌复制。在这项研究中，我们表明，在携带突变型Naip 5等位基因的A/J巨噬细胞和与突变型Naip 5等位基因同源的C57 BL/6（B6）巨噬细胞（B6-Naip 5（A/J））中，重组鞭毛蛋白的胞质递送激活caspase-1，但在Ipaf（-/-）细胞中不激活。与这些结果一致，当用军团菌感染时，A/J和B6-Naip 5（A/J）巨噬细胞诱导高水平的半胱天冬酶-1活化和IL-1 β分泌。此外，在A/J巨噬细胞中功能性Naip 5等位基因的转基因表达不改变军团菌诱导的半胱天冬酶-1活化和IL-1 β分泌。值得注意的是，尽管正常的半胱天冬酶-1活化，缺陷的Naip 5信号传导使得B6-Naip 5（A/J）巨噬细胞允许军团菌增殖。这些结果表明，细胞内军团菌复制的限制比以前认识到的更复杂，需要Ipaf依赖性caspase-1激活以及功能性Naip 5信号传导。
Similar to Ipaf and caspase-1, the Nod-like receptor protein Naip5 restricts intracellular proliferation of Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires' disease. Thus, Naip5 has been suggested to regulate Legionella replication inside macrophages through the activation of caspase-1. In this study, we show that cytosolic delivery of recombinant flagellin activated caspase-1 in A/J macrophages carrying a mutant Naip5 allele, and in C57BL/6 (B6) macrophages congenic for the mutant Naip5 allele (B6-Naip5(A/J)), but not in Ipaf(-/-) cells. In line with these results, A/J and B6-Naip5(A/J) macrophages induced high levels of caspase-1 activation and IL-1 beta secretion when infected with Legionella. In addition, transgenic expression of a functional Naip5 allele in A/J macrophages did not alter Legionella-induced caspase-1 activation and IL-1 beta secretion. Notably, defective Naip5 signaling renders B6-Naip5(A/J) macrophages permissive for Legionella proliferation despite normal caspase-1 activation. These results indicate that the restriction of intracellular Legionella replication is more complex than previously appreciated and requires both Ipaf-dependent caspase-1 activation as well as functional Naip5 signaling.