Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.
J Biol Chem. 2018 Mar 30;293(13):4893-4900. doi: 10.1074/jbc.RA117.001105. Epub 2018 Feb 6.
Inflammasomes are cytosolic complexes that mature and secrete the inflammatory cytokines interleukin 1β (IL-1β) and IL-18 and induce pyroptosis. The NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome detects many pathogen- and danger-associated molecular patterns, and reactive oxygen species (ROS)/reactive nitrogen species (RNS) have been implicated in its activation. The phenazine pyocyanin (PCN) is a virulence factor of and generates superoxide in cells. Here we report that PCN inhibits IL-1β and IL-18 release and pyroptosis upon NLRP3 inflammasome activation in macrophages by preventing speck formation and Caspase-1 maturation. Of note, PCN did not regulate the AIM2 (absent in melanoma 2) or NLRC4 inflammasomes or tumor necrosis factor (TNF) secretion. Imaging of the fluorescent glutathione redox potential sensor Grx1-roGFP2 indicated that PCN provokes cytosolic and nuclear but not mitochondrial redox changes. PCN-induced intracellular ROS/RNS inhibited the NLRP3 inflammasome posttranslationally, and hydrogen peroxide or peroxynitrite alone were sufficient to block its activation. We propose that cytosolic ROS/RNS inhibit the NLRP3 inflammasome and that PCN's anti-inflammatory activity may help evade immune recognition.
炎症小体是细胞浆复合物，可成熟并分泌炎症细胞因子白细胞介素 1β（IL-1β）和白细胞介素 18，并诱导细胞焦亡。NLRP3（NACHT、LRR 和 PYD 结构域包含蛋白 3）炎症小体检测许多病原体和危险相关分子模式，活性氧（ROS）/活性氮（RNS）被认为参与其激活。吩嗪绿脓菌素（PCN）是 的一种毒力因子，可在细胞中产生超氧阴离子。在这里，我们报告 PCN 通过防止斑点形成和 Caspase-1 成熟来抑制巨噬细胞中 NLRP3 炎症小体激活后的 IL-1β和 IL-18 释放和细胞焦亡。值得注意的是，PCN 不调节 AIM2（黑色素瘤 2 缺失）或 NLRC4 炎症小体或肿瘤坏死因子（TNF）分泌。荧光谷胱甘肽氧化还原电位传感器 Grx1-roGFP2 的成像表明，PCN 引发细胞质和核质但不引发线粒体的氧化还原变化。PCN 诱导的细胞内 ROS/RNS 在后翻译水平上抑制 NLRP3 炎症小体，而过氧化氢或过氧亚硝酸盐单独足以阻断其激活。我们提出，细胞质 ROS/RNS 抑制 NLRP3 炎症小体，PCN 的抗炎活性可能有助于 逃避免疫识别。
