Innate immune responses to TREM-1 activation: Overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide
Innate immune responses to TREM-1 activation: Overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide
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DOI：
10.4049/jimmunol.180.5.3520
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Lin, Lih-Ling
中科院分区：
文献类型：
--
作者：
Dower, Ken;Ellis, Debra K.;Lin, Lih-Ling
TREM-1（髓样细胞上表达的触发受体-1）是在单核细胞、巨噬细胞和嗜中性粒细胞上表达的孤儿免疫受体。TREM-1与含有ITAM的衔接蛋白DAP 12/TYROBP结合并通过其发出信号。通过受体交联的TREM-1活化已被证明是促炎性的，并且放大了对TLR配体如细菌LPS的一些细胞应答。为了研究TREM-1激活的细胞后果，我们已经表征了与LPS相比和与LPS组合的响应于TREM-1交联的人单核细胞中的全局基因表达变化。TREM-1活化和LPS均上调趋化因子、细胞因子、基质金属蛋白酶和PTGS/COX 2，与核心炎症反应一致。然而，选择性地诱导其他免疫调节因子，包括SPP 1和CSF 1（即，M-CSF）和IL-23和CSF 3（即，G-CSF）。此外，TREM-1激活和LPS之间的串扰发生在多个水平上。虽然GM-CSF蛋白产生中的协同作用反映在相当的mRNA丰度中，但IL-1 β蛋白产生中的可比协同作用不是。TREM-1活化还减弱了一些LPS靶基因的诱导，包括编码IL-12细胞因子家族亚基的那些。在测试时，阳性TREM-1输出被PI 3 K抑制剂渥曼青霉素大大降低，而这种衰减在很大程度上是PI 3 K无关的。这些实验提供了TREM-1激活的细胞后果的详细分析，并突出了ITAM和TLR介导的信号传导之间的信号整合的复杂性。
TREM-1 (triggering receptor expressed on myeloid cells-1) is an orphan immunoreceptor expressed on monocytes, macrophages, and neutrophils. TREM-1 associates with and signals via the adapter protein DAP12/TYROBP, which contains an ITAM. TREM-1 activation by receptor cross-linking has been shown to be proinflammatory and to amplify some cellular responses to TLR ligands such as bacterial LPS. To investigate the cellular consequences of TREM-1 activation, we have characterized global gene expression changes in human monocytes in response to TREM-1 cross-linking in comparison to and combined with LPS. Both TREM-1 activation and LPS up-regulate chemokines, cytokines, matrix metalloproteases, and PTGS/COX2, consistent with a core inflammatory response. However, other immunomodulatory factors are selectively induced, including SPP1 and CSF1 (i.e., M-CSF) by TREM-1 activation and IL-23 and CSF3 (i.e., G-CSF) by LPS. Additionally, cross-talk between TREM-1 activation and LPS occurs on multiple levels. Although synergy in GM-CSF protein production is reflected in commensurate mRNA abundance, comparable synergy in IL-1 beta protein production is not. TREM-1 activation also attenuates the induction of some LPS target genes, including those that encode IL-12 cytokine family subunits. Where tested, positive TREM-1 outputs are greatly reduced by the PI3K inhibitor wortmannin, whereas this attenuation is largely PI3K independent. These experiments provide a detailed analysis of the cellular consequences of TREM-1 activation and highlight the complexity in signal integration between ITAM- and TLR-mediated signaling.