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El sensor de células necróticas Clec4e promueve un fenotipo de macrófago proaterogénico a través de la activación de

Marc Clément¹, Gemma Basatemur¹, Leanne Masters¹

¹From Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK (M.C., G.B., L.M., L.B., J.G., Z.M.); Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France (P.B., Z.M.); Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan (T.I.); Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center and Department of Dermatology (M.K.), Eberhard Karls University, Tübingen, Germany; and Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Kyushu, Japan (S.Y.).

|September 3, 2016

Resumen

La activación del receptor de lectina tipo C 4e (Clec4e) por las células necróticas conduce a la aterosclerosis al deteriorar el eflujo de colesterol y promover la inflamación. La orientación de la señalización Clec4e puede ofrecer nuevas estrategias terapéuticas para las enfermedades cardiovasculares.

Área de la Ciencia:

Inmunología
Biología cardiovascular
La medicina molecular

Sus antecedentes:

La expansión de la lesión aterosclerótica implica un núcleo necrótico rico en lípidos, vinculado a complicaciones.
Los mecanismos moleculares de la formación de núcleos necróticos, que involucran el manejo de lípidos y la inflamación, no se comprenden completamente.
El receptor de lectina tipo C 4e (Clec4e) detecta los patrones de las células necróticas y promueve la inflamación.

Objetivo del estudio:

Investigar el papel causal de la activación de Clec4e por necrosis en la aterogénesis.
Evaluar el impacto de Clec4e en la función de los macrófagos y el desarrollo de la aterosclerosis.

Principales métodos:

Análisis in vitro de la activación de Clec4e en las funciones de los macrófagos.
Estudios in vivo con ratones con deficiencia de receptores de lipoproteínas de baja densidad (Ldlr-/).
Manipulación genética de Clec4e, Chop, Ire1a y Atf3 en modelos de ratón.

Principales resultados:

Clec4e se expresa y se activa en lesiones ateroscleróticas en humanos y ratones.
La señalización de Clec4e inhibe el eflujo de colesterol, induce estrés en el retículo endoplasmático y promueve la inflamación en los macrófagos.
La deficiencia de Clec4e en células derivadas de la médula ósea reduce significativamente la aterosclerosis en ratones Ldlr-/-.

Conclusiones:

Clec4e juega un papel no redundante en la coordinación de las vías clave en la aterosclerosis.
Clec4e puede ser un objetivo terapéutico para la aterosclerosis y otras enfermedades inflamatorias crónicas.

Palabras clave:

la aterosclerosis Proliferación de las células inflamación Necrosis en el cuerpo

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