RESUMEN

DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status remain poorly defined. Here, we identify a microRNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/- mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a.

Asunto(s)

Moléculas de Adhesión Celular/metabolismo , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Sistema de Señalización de MAP Quinasas , MicroARNs/metabolismo , Monocitos/metabolismo , Receptores de Superficie Celular/metabolismo , Adulto , Animales , Diferenciación Celular , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Persona de Mediana Edad , Células THP-1 , Receptor Toll-Like 4/metabolismo