What is it about?

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 Listeria monocytogenes–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 Cys54 and Cys347, 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.

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Why is it important?

Using L. monocytogenes, a pathogen that has been used previously to unravel various immunological processes, we identify ROS produced by mitochondria as crucial regulators of the proinflammatory response to bacterial infection. Mechanistically, we found that mtROS-mediated disulfide linkage of NEMO was an essential regulatory step in proinflammatory signaling leading to cytokine secretion. Specifically, mtROS mediated covalent linkage of NEMO through disulfide bonds formed by Cys54 and Cys347, which is essential for activation of the IKK complex, and subsequent signaling through the ERK1/2 and NF-κB pathways that eventually leads to proinflammatory cytokine secretion.

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This page is a summary of: Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO, Science Signaling, February 2019, American Association for the Advancement of Science, DOI: 10.1126/scisignal.aar5926.
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