Netea Mihai G, Azam Tania, Ferwerda Gerben, Girardin Stephen E, Kim Soo-Hyun, Dinarello Charles A
Division of Infectious Diseases, B168 University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
J Leukoc Biol. 2006 Dec;80(6):1454-61. doi: 10.1189/jlb.1205758. Epub 2006 Aug 29.
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of a new family of myeloid receptors, encoded by a gene cluster linked to the MHC. Engagement of TREM-1 stimulates intracellular signals, resulting in activation of phagocytosis, neutrophil degranulation, and amplification of cytokine production induced by TLRs. In the present study, a novel property following engagement of TREM-1 is described, namely the amplification of cytokine production induced by the second major class of pattern recognition receptors, the NAIP, CIITA, HET-E, TP-1-leucine-rich repeat (NACHT-LRR; NLR) receptors, which recognize intracellular microorganisms through sensing their muropeptide components of peptidoglycan. The TREM-1/NLR synergism was observed for the production of TNF-alpha, IL-1beta, and IL-6, leading to an increase in cytokine production up to tenfold greater than the additive value of TREM-1 or muropeptide stimulation alone. Several putative mechanisms are proposed to be involved in the synergism between NLRs and TREM-1, including the increase in TREM-1 expression by NLR ligands, and of the expression of nucleotide oligomerization domain-2 receptor by TREM-1 engagement. In contrast, although caspase-1 modulates IL-1beta and IL-6 production after stimulation with anti-TREM-1 antibodies or NLR ligands, it does not appear to be responsible for the synergism between these two pathways. These findings demonstrate that TREM-1 acts on both major recognition pathways of bacterial structures: the extracellular TLR receptors, and the intracellular NLR molecules. This latter finding supports the concept that TREM-1 provides optimal amplification of cytokine-induced inflammation during the initiation of host defense.
髓样细胞表达的触发受体-1（TREM-1）是髓样受体新家族的成员，由与MHC相连的基因簇编码。TREM-1的激活会刺激细胞内信号，导致吞噬作用激活、中性粒细胞脱颗粒以及Toll样受体（TLR）诱导的细胞因子产生增加。在本研究中，描述了TREM-1激活后的一种新特性，即由第二类主要的模式识别受体——NAIP、CIITA、HET-E、TP-1富含亮氨酸重复序列（NACHT-LRR；NLR）受体诱导的细胞因子产生增加，这些受体通过感知肽聚糖的胞壁肽成分来识别细胞内微生物。观察到TREM-1/NLR协同作用可产生肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6），导致细胞因子产生增加，比单独的TREM-1或胞壁肽刺激的相加值高出多达10倍。提出了几种可能参与NLR与TREM-1之间协同作用的机制，包括NLR配体增加TREM-1的表达，以及TREM-1激活增加核苷酸寡聚化结构域-2受体的表达。相比之下，虽然半胱天冬酶-1在抗TREM-1抗体或NLR配体刺激后调节IL-1β和IL-6的产生，但它似乎不负责这两条途径之间的协同作用。这些发现表明，TREM-1作用于细菌结构的两种主要识别途径：细胞外TLR受体和细胞内NLR分子。后一发现支持了TREM-1在宿主防御启动期间为细胞因子诱导的炎症提供最佳放大作用的概念。
