RESUMEN
Neutrophils release neutrophil extracellular traps (NETs) in response to numerous pathogenic microbes as the last suicidal resource (NETosis) in the fight against infection. Apart from the host defense function, NETs play an essential role in the pathogenesis of various autoimmune and inflammatory diseases. Therefore, understanding the molecular mechanisms of NETosis is important for regulating aberrant NET release. The initiation of NETosis after the recognition of pathogens by specific receptors is mediated by an increase in intracellular Ca2+ concentration, therefore, the use of Ca2+ ionophore A23187 can be considered a semi-physiological model of NETosis. Induction of NETosis by various stimuli depends on reactive oxygen species (ROS) produced by NADPH oxidase, however, NETosis induced by Ca2+ ionophores was suggested to be mediated by ROS produced in mitochondria (mtROS). Using the mitochondria-targeted antioxidant SkQ1 and specific inhibitors of NADPH oxidase, we showed that both sources of ROS, mitochondria and NADPH oxidase, are involved in NETosis induced by A23187 in human neutrophils. In support of the critical role of mtROS, SkQ1-sensitive NETosis was demonstrated to be induced by A23187 in neutrophils from patients with chronic granulomatous disease (CGD). We assume that Ca2+-triggered mtROS production contributes to NETosis either directly (CGD neutrophils) or by stimulating NADPH oxidase. The opening of the mitochondrial permeability transition pore (mPTP) in neutrophils treated by A23187 was revealed using the electron transmission microscopy as a swelling of the mitochondrial matrix. Using specific inhibitors, we demonstrated that the mPTP is involved in mtROS production, NETosis, and the oxidative burst induced by A23187.
Asunto(s)
Trampas Extracelulares/metabolismo , Enfermedad Granulomatosa Crónica/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , NADPH Oxidasa 2/metabolismo , Neutrófilos/metabolismo , Estallido Respiratorio/fisiología , Adolescente , Calcimicina/farmacología , Calcio/metabolismo , Cationes Bivalentes/metabolismo , Células Cultivadas , Niño , Transporte de Electrón , Depuradores de Radicales Libres/farmacología , Enfermedad Granulomatosa Crónica/sangre , Voluntarios Sanos , Humanos , Mutación con Pérdida de Función , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Proteínas de Transporte de Membrana Mitocondrial/ultraestructura , Poro de Transición de la Permeabilidad Mitocondrial , NADPH Oxidasa 2/antagonistas & inhibidores , NADPH Oxidasa 2/genética , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/ultraestructura , Oxidación-Reducción/efectos de los fármacos , Plastoquinona/análogos & derivados , Plastoquinona/farmacología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Estallido Respiratorio/efectos de los fármacosRESUMEN
The pathogenesis of many autoimmune diseases is initially based on a redundant or prolonged activation of the innate immune system. It was suggested that an excessive activation of the innate immunity is often the result of a chronic inflammatory process in the organism. This inflammation can be induced by exogenous and endogenous alarm factors, or alarmins. We believe that the recently discovered neutrophil extracellular traps, or NETs, completely meet the criteria of alarmins. This review summarizes current knowledge concerning the general characteristics of NETs, their antimicrobial properties, and their role in the development of chronic inflammatory processes that underlie the pathogenesis of psoriasis and atherosclerosis. Studies on the NETosis can provide the foundation for developing new diagnostic methods and effective treatment of chronic inflammatory and autoimmune diseases.