Otto 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.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, 138648 Singapore, Singapore.
Cell Rep. 2020 Mar 17;30(11):3793-3805.e5. doi: 10.1016/j.celrep.2020.02.077.
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-SIGN mo-DCs and lead to development of proinflammatory DC-SIGN 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.
树突状细胞特异性细胞间黏附分子-3 结合非整合素 (DC-SIGN) 来源的树突状细胞 (mo-DC) 在细菌感染和炎症性疾病中发挥重要作用，但调节其分化和促炎状态的因素仍未完全明确。在这里，我们鉴定出一种 microRNA，miR-181a，以及一个同时调节 DC-SIGN 表达获得和 DC-SIGN mo-DC 激活状态的分子机制。具体而言，我们表明 miR-181a 在 mo-DC 终末分化过程中促进 DC-SIGN 表达，并限制其对 TLR 触发和 CD40 配体的敏感性和反应性。从机制上讲，miR-181a 在 mo-DC 中维持 ERK-MAPK 信号，从而维持高水平的 DC-SIGN 和高激活阈值。在 mo-DC 分化过程中，炎症信号诱导的 miR-181a 水平降低，不支持 DC-SIGN mo-DC 所需的高磷酸化 ERK 信号转导，导致促炎型 DC-SIGN mo-DC 的发育。总之，我们的研究表明，高表达的 DC-SIGN 和高激活阈值在 mo-DC 中是相关的，并且由 miR-181a 同时维持。
