Autophagy plays an important role in immunity to microbial pathogens. The autophagy system can target bacteria in phagosomes, promoting phagosome maturation and preventing pathogen escape into the cytosol. Recently, Toll-like receptor (TLR) signaling from phagosomes was found to initiate their targeting by the autophagy system, but the mechanism by which TLR signaling activates autophagy is unclear. Here we show that autophagy targeting of phagosomes is not exclusive to those containing TLR ligands. Engagement of either TLRs or the Fc␥ receptors (Fc␥Rs) during phagocytosis induced recruitment of the autophagy protein LC3 to phagosomes with similar kinetics. Both receptors are known to activate the NOX2 NADPH oxidase, which plays a central role in microbial killing by phagocytes through the generation of reactive oxygen species (ROS). We found that NOX2-generated ROS are necessary for LC3 recruitment to phagosomes. Antibacterial autophagy in human epithelial cells, which do not express NOX2, was also dependent on ROS generation. These data reveal a coupling of oxidative and nonoxidative killing activities of the NOX2 NADPH oxidase in phagocytes through autophagy. Furthermore, our results suggest a general role for members of the NOX family in regulating autophagy.phagosome ͉ reactive oxygen species ͉ TLR ͉ innate immunity ͉ Salmonella
Autophagy is a degradative pathway that involves delivery of cytoplasmic components, including proteins, organelles, and invaded microbes to the lysosome for digestion. Autophagy is implicated in the pathology of various human diseases. The association of autophagy to inflammatory bowel diseases is consistent with recent discoveries of its role in immunity. A complex of signaling pathways control the induction of autophagy in different cellular contexts. Reactive oxygen species (ROS) are highly reactive oxygen free radicals or non-radical molecules that are generated by multiple mechanisms in cells, with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and mitochondria as major cellular sources. These ROS are important signaling molecules that regulate many signal-transduction pathways and play critical roles in cell survival, death, and immune defenses. ROS were recently shown to activate starvation-induced autophagy, antibacterial autophagy, and autophagic cell death. Current findings implicate ROS in the regulation of autophagy through distinct mechanisms, depending on cell types and stimulation conditions. Conversely, autophagy can also suppress ROS production. Understanding the mechanisms behind ROS-induced autophagy will provide significant therapeutic implications for related diseases.
Reactive oxygen species (ROS) have long been studied in the context of their direct toxic effects on cells. As a result, ROS have conventionally been thought of as a necessary nuisance to aerobic living. However, in recent years, much work has been done to examine the contribution of ROS to the field of immunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases were identified as one of the key sources of ROS in immune cells. The NOX2 NADPH oxidase in particular has been assigned multiple roles, functioning as a source of antimicrobial ROS, an activator of many signaling pathways, a participant in chemotaxis, an immune modulator, and a critical player in the initiation of antigen cross-presentation. Furthermore, recent studies have revealed a novel role for the NOX2 NADPH oxidase in the activation of autophagy, a cellular degradative pathway. Here, we examine these functions of NOX2 NADPH oxidase in immunity.
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