Nat. Immunol., published online 5 May 2013, doi:10.1038/ni.2595

Credit: NATURE IMMUNOLOGY

Clearance of microbes by the immune system requires their delivery into acidic degradative organelles, called phagolysosomes, within macrophages. Acidification of microbe-containing compartments occurs rapidly after phagocytosis and requires vacuolar H+ ATPase (V-ATPase), though the mechanism by which pH is regulated is poorly defined. To determine the nature of the acidification event, Sokolovska et al. focused on the activity of the inflammasome, a complex that is assembled after the immunological receptor NLRP3 senses pathogens or danger signals. When Staphylococcus aureus was introduced to macrophages, the authors found active caspase-1, the effector of the inflammasome, near bacteria-containing phagosomes. Caspase-1 activation required the inflammasome and occurred immediately after internalization independently of V-ATPase activity. From a bioinformatics analysis of phagosome-associated proteins, the authors identified several candidate caspase-1 substrates, including ROS-generating NADPH oxidase, NOX2, which neutralizes phagosomal pH. They verified that at least one of the predicted caspase-1 cleavage events within the NOX2 complex occurs in vivo during infection. Cleavage by caspase-1 decreases NOX2 activity and the production of ROS that is associated with phagocytosis, thereby directly controlling the accumulation of protons in the phagosome. A role in regulating phagosome pH by counteracting the buffering activity of the NOX2 complex adds a crucial function to the known roles of caspase-1 in the release of proinflammatory cytokines and immune cell death.