NLRP3 inflammasome mediates interleukin-1 production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice
NLRP3 inflammasome mediates interleukin-1 production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice
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DOI：
10.1111/imm.12704
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发表时间：
2017-04-01
期刊：
影响因子：
6.4
通讯作者：
Park, Jong-Hwan
中科院分区：
文献类型：
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作者：
Kang, Min-Jung;Jo, Sung-Gang;Park, Jong-Hwan
鲍曼不动杆菌是一种多重耐药的革兰氏阴性细菌，感染这种微生物是重症监护病房死亡的主要原因之一。炎性小体是包括半胱天冬酶-1的多蛋白寡聚体，并且它们的活化是白细胞介素-1（IL-1）成熟所需的。炎性体信号传导参与了宿主对各种微生物感染的防御，但A。鲍曼不动杆菌激活炎性小体及相关信号在宿主防御肺曲霉菌中的作用。鲍曼不动杆菌感染情况不明。我们的结果表明，NLRP 3，ASC和caspase-1，而不是NLRC 4是A.鲍曼不动杆菌诱导巨噬细胞产生IL-1。抑制剂分析显示，多种途径，包括P2 X7 R、K+流出、活性氧产生和组织蛋白酶释放，参与了巨噬细胞响应A产生IL-1。鲍曼不动杆菌。NLRP 3缺陷和caspase-1/11缺陷小鼠感染A.鲍曼不动杆菌，与野生型（WT）小鼠。然而，在WT和NLRP 3缺陷或半胱天冬酶-1/11缺陷小鼠之间，BAL液和肺中的细菌负荷相当。在NLRP 3缺陷型、半胱天冬酶-1/11缺陷型和IL-1受体缺陷型小鼠中，肺部病理学的严重程度降低，尽管这些小鼠中免疫细胞的募集和炎性细胞因子和趋化因子的产生没有改变。这些结果表明A.鲍曼不动杆菌导致NLRP 3炎性体的活化，其介导IL-1产生和肺病理学。
Acinetobacter baumannii is a multi-drug resistant, Gram-negative bacteria and infection with this organism is one of the major causes of mortality in intensive care units. Inflammasomes are multiprotein oligomers that include caspase-1, and their activation is required for maturation of interleukin-1 (IL-1). Inflammasome signalling is involved in host defences against various microbial infections, but the precise mechanism by which A. baumannii activates inflammasomes and the roles of relevant signals in host defence against pulmonary A. baumannii infection are unknown. Our results showed that NLRP3, ASC and caspase-1, but not NLRC4, are required for A. baumannii-induced production of IL-1 in macrophages. An inhibitor assay revealed that various pathways, including P2X7R, K+ efflux, reactive oxygen species production and release of cathepsins, are involved in IL-1 production in macrophages in response to A. baumannii. Interleukin-1 production in bronchoalveolar lavage (BAL) fluid was impaired in NLRP3-deficient and caspase-1/11-deficient mice infected with A. baumannii, compared with that in wild-type (WT) mice. However, the bacterial loads in BAL fluid and lungs were comparable between WT and NLRP3-deficient or caspase-1/11-deficient mice. The severity of lung pathology was reduced in NLRP3- deficient, caspase-1/11- deficient and IL-1-receptor-deficient mice, although the recruitment of immune cells and production of inflammatory cytokines and chemokines were not altered in these mice. These findings indicate that A. baumannii leads to the activation of NLRP3 inflammasome, which mediates IL-1 production and lung pathology.