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Published on: May 31, 2018
miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived
Clarice X Lim1, Bernett Lee2, Olivia Geiger3
1Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria; DK Inflammation & Immunity Program, Medical University of Vienna, 1090 Vienna, Austria.
Abstract:
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.
Insights
MicroRNA miR-181a regulates DC-SIGN expression and activation threshold in monocyte-derived dendritic cells (mo-DCs). This finding is crucial for understanding bacterial infections and inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Monocyte-derived dendritic cells (mo-DCs) expressing DC-SIGN are vital in bacterial infections and inflammatory conditions.
- Factors controlling DC-SIGN+ mo-DC differentiation and inflammatory status are not fully understood.
Purpose of the Study:
- To identify microRNA and molecular mechanisms regulating DC-SIGN expression and activation state in mo-DCs.
- To elucidate the role of miR-181a in DC-SIGN+ mo-DC differentiation and function.
Main Methods:
- Investigated the role of miR-181a in mo-DC differentiation using molecular biology techniques.
- Analyzed the impact of miR-181a on DC-SIGN expression and cellular signaling pathways (ERK-MAPK).
- Examined mo-DC responsiveness to TLR triggering and CD40 ligation under varying miR-181a levels.
Main Results:
- miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation.
- miR-181a sustains ERK-MAPK signaling, maintaining high DC-SIGN levels and a high activation threshold.
- Low miR-181a levels result in proinflammatory DC-SIGNlo/- mo-DCs with impaired signaling.
Conclusions:
- High DC-SIGN expression and activation threshold in mo-DCs are simultaneously maintained by miR-181a.
- miR-181a acts as a key regulator linking DC-SIGN expression and mo-DC activation state.
- Understanding this mechanism offers insights into inflammatory diseases and bacterial infections.
