Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935 Cologne, Germany.
Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Sci Signal. 2019 Feb 12;12(568):eaar5926. doi: 10.1126/scisignal.aar5926.
A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). We identified the inhibitor of κB (IκB) kinase (IKK) complex regulatory subunit NEMO [nuclear factor κB (NF-κB) essential modulator] as a target for mtROS. Specifically, mtROS induced intermolecular covalent linkage of NEMO through disulfide bonds formed by Cys and Cys, which was essential for activation of the IKK complex and subsequent signaling through the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and NF-κB pathways that eventually led to the secretion of proinflammatory cytokines. We thus identify mtROS-dependent disulfide linkage of NEMO as an essential regulatory step of the proinflammatory response of macrophages to bacterial infection.
巨噬细胞在感染过程中的一个主要功能是启动炎症反应，导致细胞因子的分泌，帮助协调免疫反应。在这里，我们确定活性氧（ROS）是导致感染巨噬细胞细胞因子分泌的炎症信号的关键介质。NADPH 氧化酶（Noxes）产生的 ROS，如 Nox2，是巨噬细胞对入侵病原体反应的关键组成部分；然而，我们的数据表明，介导炎症信号的 ROS 是由线粒体（mtROS）产生的。我们确定了 IκB 激酶（IKK）复合物调节亚基 NEMO（核因子κB（NF-κB）必需调节剂）作为 mtROS 的靶点。具体来说，mtROS 通过 Cys 和 Cys 形成的二硫键诱导 NEMO 的分子间共价连接，这对于 IKK 复合物的激活以及随后通过细胞外信号调节蛋白激酶 1 和 2（ERK1/2）和 NF-κB 途径的信号转导至关重要，最终导致促炎细胞因子的分泌。因此，我们确定 mtROS 依赖性的 NEMO 二硫键连接是巨噬细胞对细菌感染的炎症反应的一个必要的调节步骤。
