miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

Abstract

Summary: 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. : DC-SIGN+ mo-DCs play important roles in bacterial infections and inflammatory diseases, but the factors regulating differentiation and activation remain poorly defined. Lim et al. show that miR-181a simultaneously fine-tunes DC-SIGN+ mo-DC differentiation/activation by promoting ERK-MAPK signaling, which sustains DC-SIGN expression and limits its responsiveness to TLR4 triggering and inflammatory stimuli. Keywords: DC-SIGN, inflammation, monocyte-derived, mo-DC, ulcerative colitis, DC-SIGN+ mo-DC, miR-181a, terminal mo-DC differentiation