FIG. 4.

Schematic representation of the complexities of the various subcellular compartments of ROS production and ROS targets that impact on immune system function. Viruses that internalize via endocytosis are sensed by endosomally located TLR7 for ssRNA viruses and TLR9 for DNA viruses. In addition to driving endosomal NOX2 oxidase, activation of TLR7 drives transcription factors including IRF-7 and NF-κB that are essential for the induction of antiviral cytokines (IFNα/β) and proinflammatory cytokines (IL-1β, IL-6), respectively. TLR7 mediates ROS generation via PKC, and the H₂O₂ generated within endosomal compartments by NOX2 targets the TLR7 cysteine 98 on the ectodomain to dampen antiviral signaling networks. Large bacteria and fungi can stimulate the production of extracellular superoxide at the level of the plasma membrane. Alternatively, bacteria and fungi (small) can be internalized via phagocytosis initiating phagosomal superoxide production by NOX2 oxidase and then conversion to H₂O₂ and HOCl via MPO (in neutrophils, mainly). Along with proteases, ROS are thought to “kill” the invading bacteria or fungi. In addition, phagosomal ROS oxidize the p50 protein subunit of NF-κB leading to ubiquitination and degradation of p50. Within the phagosome, engagement of bacterial sensors TLR1, TLR2, or TLR4 causes translocation of TRAF to the mitochondria that binds to ECSIT, facilitating the generation of mtROS to enhance bacterial killing. Mitochondrial H₂O₂ targets MAVS for activation of IRF-7 and NF-κB. mtROS may also activate NLRP3 leading to inflammation activation. ECSIT, evolutionarily conserved signaling intermediate in toll pathways; IFN, interferon; IL, interleukin; IRF-7, interferon regulatory factor 7; MAVS, mitochondrial antiviral signaling; mtROS, mitochondrial ROS; NF-κB, nuclear factor kappa B; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; TRAF, tumor necrosis factor receptor-associated factor. Color images are available online.