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Oxysterol La restricción de la síntesis de colesterol impide la activación del inflamatorio AIM2

Eric V Dang¹, Jeffrey G McDonald², David W Russell²

¹Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143-0795, USA.

|October 17, 2017

Resumen

El interferón de tipo I restringe la inflamación mediante la regulación al alza de la colesterol-25-hidroxilasa (Ch25h). Este estudio muestra que la producción de 25-hidroxicolesterol (25-HC) impide la activación del inflamatorio, manteniendo la integridad mitocondrial y evitando la activación de AIM2.

Área de la Ciencia:

Inmunología
Biología celular
Las vías metabólicas

Sus antecedentes:

La señalización de interferón tipo I restringe la inflamación inducida por la IL-1β a través de la represión de Ch25h y SREBP.
El vínculo molecular entre el metabolismo de los lípidos y la producción de IL-1β no se comprende completamente.

Objetivo del estudio:

Investigar el papel del 25-hidroxicolesterol (25-HC) en la activación del inflamatorio y la producción de IL-1β.
Para aclarar la conexión entre el metabolismo lipídico, la integridad mitocondrial y el inflamatorio AIM2.

Principales métodos:

Los cultivos de macrófagos estimulados con una infección bacteriana o LPS.
Análisis de la expresión y actividad de Ch25h y SREBP.
Evaluación de la síntesis y el contenido de colesterol.
Medición de la liberación de IL-1β y la activación del inflamatorio (dependiente del AIM2).
Análisis de la función mitocondrial y evaluación de la liberación de ADN mitocondrial.

Principales resultados:

La producción de macrófagos 25-HC es esencial para prevenir la activación del inflamatorio AIM2.
La upregulación de Ch25h por LPS/infección reprime la SREBP2 y la síntesis de colesterol.
El aumento del colesterol de los macrófagos desencadena la liberación de IL-1β dependiente de AIM2.
La deficiencia de Ch25h conduce a una alteración de la respiración mitocondrial y a la liberación citosólica del ADN mitocondrial.
La deficiencia de AIM2 rescata la actividad inflamatoria elevada en los macrófagos con deficiencia de Ch25h.

Conclusiones:

Los macrófagos activados utilizan el 25-HC en un circuito de retroalimentación antiinflamatoria.
Este circuito preserva la integridad mitocondrial y previene la activación aberrante del inflamatorio AIM2.
El metabolismo de los lípidos, particularmente el colesterol, juega un papel crítico en la regulación de las respuestas inmunes innatas.

Palabras clave:

El 25-hidroxicolesterol AIM2 (en inglés)C25h y IL-1β, también conocido como IL-1 El proyecto SREBP el colesterol El inflamatorio Los macrófagos Las mitocondrias el oxicosterol

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