Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1β response to Pseudomonas aeruginosa
Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1β response to Pseudomonas aeruginosa
复制标题
DOI：
10.1152/ajplung.00228.2015
复制
发表时间：
2015-10-15
影响因子：
4.9
通讯作者：
Berwin, Brent
中科院分区：
文献类型：
--
作者：
Patankar, Yash R.;Mabaera, Rodwell;Berwin, Brent
NLRC 4炎性体负责响应铜绿假单胞菌感染的巨噬细胞的IL-1 β加工。因此，我们假设缺乏ASC（巨噬细胞体外产生IL-1 β所必需的NLRC 4炎性体衔接蛋白）的小鼠将优先受到保护，免受依赖于细菌3型分泌系统（T3 SS）活性的高炎症致死性攻击。我们在此报道，缺乏ASC不会赋予对铜绿假单胞菌急性感染的优先保护，并且ASC（-/-）小鼠能够产生与C57 BL/6小鼠相当的稳健量的IL-1 β。我们现在确定中性粒细胞代表了急性肺炎和腹膜炎模型中感染急性期IL-1 β产生的ASC非依赖性来源。因此，ASC（-/-）小鼠中中性粒细胞的消耗导致体内IL-1 β产生的显著缺陷。肺中性粒细胞IL-1 β反应主要依赖于caspase-1，这与眼部感染的数据形成对比。因此，这些研究确定了独立于ASC的中性粒细胞产生IL-1 β的非经典机制，并证明了在急性肺炎和腹膜炎期间，中性粒细胞作为响应急性铜绿假单胞菌感染的IL-1 β的重要来源的第一生理贡献。
The NLRC4 inflammasome is responsible for IL-1 beta processing by macrophages in response to Pseudomonas aeruginosa infection. We therefore hypothesized that mice that lack ASC, an NLRC4 inflammasome adaptor protein necessary for in vitro IL-1 beta production by macrophages, would be preferentially protected from a hyperinflammatory lethal challenge that is dependent on bacterial type three secretion system (T3SS) activity. We report herein that lack of ASC does not confer preferential protection in response to P. aeruginosa acute infection and that ASC(-/-) mice are capable of producing robust amounts of IL-1 beta comparable with C57BL/6 mice. We now identify that neutrophils represent the ASC-independent source of IL-1 beta production during the acute phases of infection both in models of acute pneumonia and peritonitis. Consequently, depletion of neutrophils in ASC(-/-) mice leads to a marked deficit in IL-1 beta production in vivo. The pulmonary neutrophil IL-1 beta response is predominantly dependent on caspase-1, which contrasts with data derived from ocular infection. These studies therefore identify a noncanonical mechanism of IL-1 beta production by neutrophils independent of ASC and demonstrate the first physiological contribution of neutrophils as an important source of IL-1 beta in response to acute P. aeruginosa infection during acute pneumonia and peritonitis.