TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

By A. West, I. Brodsky, C. Rahner, D. Woo, H. Erdjument‐Bromage, Paul Tempst, M. Walsh, Yongwon Choi, G. Shadel, S. Ghosh. Nature, 2011

1,583 citations recorded by the source corpus.

Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/c0de62d366578fa7d37ef4cccdff8d9367123685

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Citations in the corpus

The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “TRAF6 can also result in the ubiquitination of ECSIT and increase mitochondrial and cellular TLR-induced ROS generation.(238) Recently, USP4 has been identified as a new DUB of TRAF6 and can negatively regulate the NF-κB signaling pathway.”
The inflammasome: an integrated view (2011, background): “This finding was interpreted as a mechanism that would allow mitochondrial ROS to contribute to pathogen killing (106).”
Metabolic Reprograming in Macrophage Polarization (2014, positive): “for this is provided when treating macrophages with the electron transport chain inhibitors rotenone and antimycin A as this mimics the effects of toll-like receptor (TLR) agonists in driving ROS production from the mitochondria (10).”
Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. (2012, background): “More recent experiments have implicated ECSIT in the LPS-stimulated production of reactive oxygen intermediates (319).”
The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases (2016, neutral): “of mitochondrial ROS and phagocytosis activity [99].”
Microglial M1/M2 polarization and metabolic states (2016, background): “A key feature of M1 macrophages is associated with their production of ROS to facilitate killing of phagocytosed bacteria (West et al., 2011).”
Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. (2012, result): “This finding dovetails with a recent report showing that TLR signaling enhances mtROS production (West et al., 2011).”
Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress versus Signal Transduction (2015, neutral): “[73] showed that overexpressing”
Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “4 In addition, dysfunctional mitochondrial are closely interrelated to a range of disease and pathology including metabolic diseases, neurodegenerative disorders and cancers, which are broadly characterized by impaired mitochondrial function.”