Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages
Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages
复制标题
DOI：
10.1038/ni1346
复制
发表时间：
2006-06-01
影响因子：
30.5
通讯作者：
Nunez, Gabriel
中科院分区：
文献类型：
--
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
在哺乳动物巨噬细胞的胞质溶胶中复制的革兰氏阴性细菌可以激活导致半胱天冬酶-1切割和分泌白细胞介素1 β（一种强大的宿主应答因子）的信号传导途径。Ipaf是核苷酸结合寡聚化结构域-富含亮氨酸重复序列蛋白家族中的胞质模式识别受体，在对沙门氏菌感染的这种反应中至关重要，但Ipaf如何被细菌激活的机制仍然知之甚少。在这里，我们表明，salarium菌株缺乏鞭毛蛋白或表达突变体鞭毛蛋白是缺乏激活的caspase-1和白细胞介素1b的分泌，虽然转录因子NF-κ B依赖的白细胞介素6或趋化因子MCP-1的生产是未受损。鞭毛蛋白的巨噬细胞胞质溶胶诱导的IPAF依赖性激活的caspase-1是独立的Toll样受体5，需要识别的细胞外鞭毛蛋白。在巨噬细胞耐受先前暴露于脂多糖，废除激活NF-κ B和丝裂原活化蛋白激酶，沙门氏菌感染仍然激活半胱天冬酶-1。因此，检测鞭毛蛋白通过Ipaf诱导caspase-1激活独立的Toll样受体5在沙门氏菌感染和脂多糖耐受的巨噬细胞。
Gram-negative bacteria that replicate in the cytosol of mammalian macrophages can activate a signaling pathway leading to caspase-1 cleavage and secretion of interleukin 1 beta, a powerful host response factor. Ipaf, a cytosolic pattern-recognition receptor in the family of nucleotide-binding oligomerization domain-leucine-rich repeat proteins, is critical in such a response to salmonella infection, but the mechanism of how Ipaf is activated by the bacterium remains poorly understood. Here we demonstrate that salmonella strains either lacking flagellin or expressing mutant flagellin were deficient in activation of caspase-1 and in interleukin 1b secretion, although transcription factor NF-kappa B-dependent production of interleukin 6 or the chemokine MCP-1 was unimpaired. Delivery of flagellin to the macrophage cytosol induced Ipaf-dependent activation of caspase-1 that was independent of Toll-like receptor 5, required for recognition of extracellular flagellin. In macrophages made tolerant by previous exposure to lipopolysaccharide, which abrogates activation of NF-kappa B and mitogen-activated protein kinases, salmonella infection still activated caspase-1. Thus, detection of flagellin through Ipaf induces caspase-1 activation independently of Toll-like receptor 5 in salmonella-infected and lipopolysaccharide-tolerized macrophages.