RESUMO
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.
Assuntos
Proteínas de Transporte/imunologia , Caspase 1/imunologia , Inflamassomos/imunologia , Glicoproteínas de Membrana/imunologia , NADPH Oxidases/imunologia , Fagossomos/imunologia , Animais , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Células Cultivadas , Ativação Enzimática/imunologia , Citometria de Fluxo , Células HEK293 , Interações Hospedeiro-Patógeno/imunologia , Humanos , Concentração de Íons de Hidrogênio , Immunoblotting , Inflamassomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fagocitose/imunologia , Fagossomos/metabolismo , Fagossomos/microbiologia , Fagossomos/ultraestrutura , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologiaRESUMO
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.
Assuntos
Caspase 1/metabolismo , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Animais , Morte Celular , Citosol/metabolismo , Humanos , Camundongos , Transdução de SinaisRESUMO
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.