Editors' ChoiceImmunology

Inflammasome Meets Phagosome

Sci. Signal.  28 May 2013:
Vol. 6, Issue 277, pp. ec123
DOI: 10.1126/scisignal.2004369

The internalization of microbes into phagosomes is an important aspect of host defense. Acidification of these organelles is required for the efficient destruction of pathogens and for the processing of antigens derived from the pathogens. Sokolovska et al. investigated whether components of the innate immune response regulated the microbicidal function of phagosomes containing the pathogen Staphylococcus aureus. Fluorescence microscopy showed that phagosomes containing S. aureus were coated with the active form of caspase-1, an effector protease activated by the NLRP3 inflammasome. This multiprotein complex is best known for its role in detecting intracellular pathogens and endogenous danger signals and eliciting the production of inflammatory cytokines. Caspase-1 was activated early after phagocytosis of S. aureus and was dependent on NLRP3 activation by the production of reactive oxygen species (ROS), which were generated during phagocytosis. Pretreatment of cells with a caspase-1 inhibitor blocked the acidification of S. aureus–containing phagosomes. Sequence analysis suggested potential phagosome-associated substrates of caspase-1, and Western blotting analysis suggested that caspase-1 cleaved and inactivated a component of the phagocyte NADPH oxidase 2 (NOX2) complex, which functions to alkalinize phagosomes. Cells deficient in NLRP3 inflammasome components that were infected with S. aureus had increased phagosomal ROS activity compared with that of infected wild-type cells, and this correlated with increased phagosomal pH. Caspase-1 was required for the acidification of phagosomes containing Gram-positive, but not Gram-negative, bacteria. Blocking caspase-1 activation in macrophages inhibited killing of internalized S. aureus, production of the inflammatory cytokine IL-6, and cross-presentation of bacterial antigens. Together, these data suggest that caspase-1, downstream of the activated NLRP3 inflammasome, functions to reduce the pH of phagosomes containing Gram-positive bacteria as part of host defense.

A. Sokolovska, C. E. Becker, W. K. E. Ip, V. A. K. Rathinam, M. Brudner, N. Paquette, A. Tanne, S. K. Vanaja, K. J. Moore, K. A. Fitzgerald, A. Lacy-Hulbert, L. M. Stuart, Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat. Immunol. 14, 543–553 (2013). [PubMed]