Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules.
Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules.
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DOI：
10.4049/jimmunol.1402713
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发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
Klesney-Tait J
中科院分区：
文献类型：
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作者：
Baruah S;Keck K;Vrenios M;Pope MR;Pearl M;Doerschug K;Klesney-Tait J
髓样细胞上表达的触发受体-1（TREM-1）对于炎症信号放大至关重要。人类有两种形式的TREM-1：与衔接子DAP 12相关的膜受体（mbTREM-1）和在感染时检测到的可溶性受体。膜受体亚型与TLR途径协同作用以促进细胞因子分泌和中性粒细胞迁移，而可溶性受体作为反调节分子发挥作用。在多种脓毒症模型中，外源性施用可溶形式的TREM-1减轻炎症并显著改善存活。尽管对可溶性TREM-1作为存活的临床预测因子和作为治疗工具的强烈兴趣，但天然可溶性TREM-1的起源仍然存在争议。利用人中性粒细胞，我们确定了一个15 kDa的TREM-1亚型的主要（嗜天青）和次要（特定）颗粒。质谱分析、ELISA和免疫印迹证实该15 kD蛋白是TREM-1的一种新型剪接变体（TREM-1 sv）。用铜绿假单胞菌、LPS或PAM（3）Cys 4刺激神经元导致脱粒和TREM-1 sv的释放。外源性TREM-1 sv的加入抑制了TREM-1受体介导的促炎细胞因子的产生。因此，这些数据表明，TREM-1亚型通过典型的膜TREM-1分子和这种新发现的颗粒亚型TREM-1 sv同时激活和抑制炎症。
Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor (mbTREM-1), associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration while the soluble receptor functions as a counter regulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1 both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Utilizing human neutrophils, we identified a 15 kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15 kD protein is a novel splice variant of TREM-1 (TREM-1sv). Neutrophil stimulation with P. aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor mediated proinflammatory cytokine production. Thus these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv.