Helming Laura, Tomasello Elena, Kyriakides Themis R, Martinez Fernando O, Takai Toshiyuki, Gordon Siamon, Vivier Eric
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Sci Signal. 2008 Oct 28;1(43):ra11. doi: 10.1126/scisignal.1159665.
Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.
由巨噬细胞融合形成的多核巨细胞是肉芽肿性炎症的一个标志。通过遗传学方法，我们发现细胞因子诱导巨细胞形成需要衔接蛋白DAP12（12kD的DNAX激活蛋白）、其相关受体髓系细胞触发受体2（TREM-2）以及下游蛋白酪氨酸激酶Syk进行信号传导，并且DAP12的过表达可增强巨噬细胞融合。我们还提供证据表明，DAP12是一种通用的巨噬细胞融合调节因子，参与调节多个巨噬细胞相关基因的表达，包括那些编码已知巨噬细胞融合介质（如DC-STAMP和钙黏蛋白1）的基因。因此，DAP12通过调节基因和蛋白质表达参与巨噬细胞编程，以诱导融合能力状态。
