TLR signalling augments macrophage bactericidal activity through mitochondrial ROS.

Reactive oxygen species are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial duanyu1670 also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for 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 mduanyu1670 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 duanyu1670 generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced duanyu1670 and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mduanyu1670 levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mduanyu1670 in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mduanyu1670 as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.

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