RESUMEN
Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense.
Asunto(s)
Proteínas Portadoras/inmunología , Caspasa 1/inmunología , Inflamasomas/inmunología , Glicoproteínas de Membrana/inmunología , NADPH Oxidasas/inmunología , Fagosomas/inmunología , Animales , Proteínas Portadoras/metabolismo , Caspasa 1/metabolismo , Células Cultivadas , Activación Enzimática/inmunología , Citometría de Flujo , Células HEK293 , Interacciones Huésped-Patógeno/inmunología , Humanos , Concentración de Iones de Hidrógeno , Immunoblotting , Inflamasomas/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Microscopía Electrónica , NADPH Oxidasa 2 , NADPH Oxidasas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Fagocitosis/inmunología , Fagosomas/metabolismo , Fagosomas/microbiología , Fagosomas/ultraestructura , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus/inmunología , Staphylococcus aureus/fisiologíaRESUMEN
Inflammasomes are cytosolic multiprotein platforms assembled in response to invading pathogens and other danger signals. Typically inflammasome complexes contain a sensor protein, an adaptor protein, and a zymogen - procaspase-1. Formation of inflammasome assembly results in processing of inactive procaspase-1 into an active cysteine-protease enzyme, caspase-1, which subsequently activates the proinflammatory cytokines, interleukins IL-1ß and IL-18, and induces pyroptosis, a highly-pyrogenic inflammatory form of cell death. Studies over the past year have unveiled exciting new players and regulatory pathways that are involved in traditional inflammasome signaling, some of them even challenging the existing dogma. This review outlines these new insights in inflammasome research and discusses areas that warrant further exploration.
Asunto(s)
Caspasa 1/metabolismo , Inflamasomas/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Animales , Muerte Celular , Citosol/metabolismo , Humanos , Ratones , Transducción de SeñalRESUMEN
Inflammasome activation is gaining recognition as an important mechanism for protection during viral infection. Here, we investigate whether Rift Valley fever virus, a negative-strand RNA virus, can induce inflammasome responses and IL-1ß processing in immune cells. We have determined that RVFV induces NLRP3 inflammasome activation in murine dendritic cells, and that this process is dependent upon ASC and caspase-1. Furthermore, absence of the cellular RNA helicase adaptor protein MAVS/IPS-1 significantly reduces extracellular IL-1ß during infection. Finally, direct imaging using confocal microscopy shows that the MAVS protein co-localizes with NLRP3 in the cytoplasm of RVFV infected cells.