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La activación no canónica del inflamasoma se dirige a la caspase-11 como objetivo
Nobuhiko Kayagaki1, Søren Warming, Mohamed Lamkanfi
1Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA. kayagaki@gene.com
Nature
|October 18, 2011
Resumen
La caspasa-11 es crucial para iniciar la respuesta inmune innata a las infecciones bacterianas mediante la activación de la caspasa-1 y la producción de IL-1β. La pérdida de caspasa-11 protege a los ratones del choque letal de la endotoxina.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- La activación del inflammasoma, que involucra a los NLR y ASC, es crítica para la producción de IL-1β e IL-18 en la inmunidad innata.
- La activación de la caspasa-1 se considera esencial para esta producción proinflamatoria de citoquinas.
Objetivo del estudio:
- Investigar el papel de la caspasa-11 en la activación del inflamatorio y la producción de citoquinas durante las infecciones bacterianas.
- Aclarar los distintos roles de la caspasa-1 y la caspasa-11 en las respuestas inmunológicas innatas.
Principales métodos:
- Se utilizaron ratones C57BL/6 y de la cepa 129, incluidos los ratones dirigidos al gen Casp11 (Casp11(-/-)).
- Se analizó la producción de IL-1β en macrófagos estimulados con varias especies bacterianas (E. coli, C. rodentium, V. cholerae), ATP y urato monosódico.
- Empleó transgenes de cromosomas artificiales bacterianos para expresar caspasa-11 en macrófagos deficientes.
Principales resultados:
- La caspasa-11 es esencial para la activación de la caspasa-1 y la producción de IL-1β en respuesta a E. coli, C. rodentium y V. cholerae.
- Los ratones de la cepa 129 poseen un locus Casp11 defectuoso, lo que afecta la producción de IL-1β.
- La caspasa-11, no la caspasa-1, media la muerte celular de los macrófagos inducida por inflamatoriosomas no canónicos.
- La pérdida de caspasa-11 confiere protección contra el desafío letal de los lipopolisacáridos.
Conclusiones:
- La caspasa-11 juega un papel crítico y no canónico en la respuesta inmune innata a las infecciones bacterianas.
- Caspase-11 orquesta las vías inflamatorias dependientes y independientes de la caspase-1.
- Es probable que existan activadores distintos para la caspasa-11 y la caspasa-1 en la activación no canónica del inflamasoma.
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