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El succinato es una señal inflamatoria que induce la IL-1β a través del HIF-1α
G M Tannahill1, A M Curtis, J Adamik
1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Nature
|March 29, 2013
Resumen
Las células inmunes innatas reprograman el metabolismo para combatir las bacterias. El succinato, un subproducto metabólico, impulsa la inflamación al aumentar la producción de interleucina-1β, una molécula clave de señalización inmune.
Área de la Ciencia:
- El inmunometabolismo es el metabolismo inmunológico.
- El metabolismo celular es el metabolismo celular.
- La inmunidad innata es la inmunidad innata.
Sus antecedentes:
- Los macrófagos son células inmunes clave que combaten las infecciones bacterianas.
- El lipopolisacárido (LPS) de las bacterias Gram-negativas desencadena cambios metabólicos en los macrófagos.
- La reprogramación metabólica influye en la respuesta inflamatoria.
Objetivo del estudio:
- Para investigar los cambios metabólicos en los macrófagos tras la activación del LPS.
- Para identificar los metabolitos clave involucrados en la inflamación inducida por el LPS.
- Comprender el papel del succinato en la señalización inmune de los macrófagos.
Principales métodos:
- Análisis de los perfiles de expresión génica en los macrófagos activados por LPS.
- Análisis metabolómico para identificar niveles alterados de metabolitos.
- La inhibición de la glucólisis mediante el uso de 2-deoxiglucosa (2-DG).
- Evaluación de la producción de citoquinas (interleucina-1β y el factor de necrosis tumoral-α).
Principales resultados:
- La activación de LPS regula hacia arriba los genes glicolíticos y regula hacia abajo los genes mitocondriales.
- Los niveles de succinato aumentan significativamente en los macrófagos activados por LPS, principalmente por la anaplerosis por glutamina y la derivación GABA.
- La inhibición de la glucólisis con 2-DG suprime la producción de interleucina-1β, pero no el factor de necrosis tumoral-α.
- El succinato inducido por LPS estabiliza el factor inducible por hipoxia-1α (HIF-1α), afectando la producción de interleucina-1β.
Conclusiones:
- El succinato actúa como un metabolito de señalización crítico en la inmunidad innata.
- El succinato mejora la producción de interleucina-1β durante la inflamación.
- Dirigirse a la glucólisis o al metabolismo de los succinatos puede ofrecer estrategias terapéuticas para las enfermedades inflamatorias.
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