Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation

• Published in: Nature microbiology Vol. 5; no. 11; pp. 1418 - 1427
• Main Authors: Deo, Pankaj, Chow, Seong H, Han, Mei-Ling, Speir, Mary, Huang, Cheng, Schittenhelm, Ralf B, Dhital, Subhash, Emery, Jack, Li, Jian, Kile, Benjamin T, Vince, James E, Lawlor, Kate E, Naderer, Thomas
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2020
• Subjects: Animals; Apoptosis; Bacterial Outer Membrane - metabolism; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2 protein; Caspase-11; Extracellular Vesicles; Gram-negative bacteria; Gram-Negative Bacteria - metabolism; Gram-Negative Bacteria - pathogenicity; Gram-Negative Bacterial Infections - immunology; IL-1β; Immune system; Inflammasomes; Inflammation; Innate immunity; Interleukin-1beta - metabolism; Macrophages; Macrophages - metabolism; Macrophages - microbiology; Macrophages - pathology; Mcl-1 protein; Membrane vesicles; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Neisseria gonorrhoeae; Protein Biosynthesis; Pyroptosis
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-020-0773-2

Sensing of microbes activates the innate immune system, depending on functional mitochondria. However, pathogenic bacteria inhibit mitochondrial activity by delivering toxins via outer membrane vesicles (OMVs). How macrophages respond to pathogenic microbes that target mitochondria remains unclear. Here, we show that macrophages exposed to OMVs from Neisseria gonorrhoeae, uropathogenic Escherichia coli and Pseudomonas aeruginosa induce mitochondrial apoptosis and NLRP3 inflammasome activation. OMVs and toxins that cause mitochondrial dysfunction trigger inhibition of host protein synthesis, which depletes the unstable BCL-2 family member MCL-1 and induces BAK-dependent mitochondrial apoptosis. In parallel with caspase-11-mediated pyroptosis, mitochondrial apoptosis and potassium ion efflux activate the NLRP3 inflammasome after OMV exposure in vitro. Importantly, in the in vivo setting, the activation and release of interleukin-1β in response to N. gonorrhoeae OMVs is regulated by mitochondrial apoptosis. Our data highlight how innate immune cells sense infections by monitoring mitochondrial health.