Mycobacterium abscessus infection leads to enhanced production of type 1 interferon and NLRP3 inflammasome activation in murine macrophages via mitochondrial oxidative stress
Fig 8
Schematic diagram showing mitochondrial oxidative stress induced by MAB-R infection of murine macrophages.
MAB-R enters macrophages by phagocytosis and leads to mitochondrial oxidative stress. Our results suggest that MAB-R infection elicits both the i) cGAS−STING−IRF3−IFN-β and ii) NLRP3 inflammasome-IL-1β pathways in murine macrophages: i) Excess formation of mtROS leads to phagosomal rupture-mediated bacterial escape into the cytosol. Cytosolic mitochondrial and mycobacterial DNA induce IFN-I production via the cGAS−STING−IRF3 pathway. ii) Additionally, oxidized mtDNA released into the cytosol leads to activation of the NLRP3 inflammasome. However, inhibition of mtROS by treatment with mito-TEMPO or CsA decreases the levels of mtROS and also leads to decreased IFN-I and IL-1β production. In addition, inhibition of mtROS leads to a reduction in MAB-R replication in phagosomes and inhibition of phagosomal rupture, which ultimately reduces bacterial survival in infected murine macrophages. These two pathways induce opposite results for host defence against MAB-R infection. IL-1β is considered to have antibacterial effects, while IFN-I is recognized to be highly detrimental to bacterial replication.