Gómez-Piña Vanesa, Soares-Schanoski Alessandra, Rodríguez-Rojas Alexandro, Del Fresno Carlos, García Felipe, Vallejo-Cremades María Teresa, Fernández-Ruiz Irene, Arnalich Francisco, Fuentes-Prior Pablo, López-Collazo Eduardo
Research Unit, La Paz Hospital, Madrid, Spain.
J Immunol. 2007 Sep 15;179(6):4065-73. doi: 10.4049/jimmunol.179.6.4065.
Triggering receptors expressed on myeloid cell (TREM) proteins are a family of cell surface receptors that participate in diverse cellular processes such as inflammation, coagulation, and bone homeostasis. TREM-1, in particular, is expressed on neutrophils and monocytes and is a potent amplifier of inflammatory responses. LPS and other microbial products induce up-regulation of cell surface-localized TREM-1 and the release of its soluble form, sTREM-1. Two hypotheses have been advanced to explain the origin of sTREM-1: alternative splicing of TREM-1 mRNA and proteolytic cleavage(s) of mature, membrane-anchored TREM-1. In this report, we present conclusive evidence in favor of the proteolytic mechanism of sTREM-1 generation. No alternative splicing forms of TREM-1 were detected in monocytes/macrophages. Besides, metalloproteinase inhibitors increased the stability of TREM-1 at the cell surface while significantly reducing sTREM-1 release in cultures of LPS-challenged human monocytes and neutrophils. We conclude that metalloproteinases are responsible for shedding of the TREM-1 ectodomain through proteolytic cleavage of its long juxtamembrane linker.
髓系细胞表达的触发受体(TREM)蛋白是一类细胞表面受体,参与多种细胞过程,如炎症、凝血和骨稳态。特别是TREM-1,在中性粒细胞和单核细胞上表达,是炎症反应的强效放大器。脂多糖和其他微生物产物可诱导细胞表面定位的TREM-1上调及其可溶性形式sTREM-1的释放。已经提出了两种假说来解释sTREM-1的起源:TREM-1 mRNA的可变剪接和成熟的膜锚定TREM-1的蛋白水解切割。在本报告中,我们提供了确凿的证据支持sTREM-1产生的蛋白水解机制。在单核细胞/巨噬细胞中未检测到TREM-1的可变剪接形式。此外,金属蛋白酶抑制剂增加了TREM-1在细胞表面的稳定性,同时显著减少了脂多糖刺激的人单核细胞和中性粒细胞培养物中sTREM-1的释放。我们得出结论,金属蛋白酶通过蛋白水解切割其长的近膜连接子负责TREM-1胞外域的脱落。