TREM-1 is a novel therapeutic target in Psoriasis. Homo sapiens

Our group recently described a population of antigen presenting cells that appear to be critical in psoriasis pathogenesis, termed inflammatory myeloid dendritic cells (CD11c+ BDCA1-). Triggering receptor expressed on myeloid cells type-1 (TREM-1) signaling was a major canonical pathway in the published transcriptome of these cells. TREM-1 is a member of the immunoglobulin superfamily, active through the DAP12 signaling pathway, with an unknown ligand. Activation through TREM-1 induces inflammatory cytokines including IL-8, MCP/CCL2 and TNF. We now show that TREM-1 was expressed in the skin of healthy and psoriatic patients, and there was increased soluble TREM-1 in the circulation of psoriasis patients. In psoriasis lesions, TREM-1 was co-localized with dendritic cells as well as CD31+ endothelial cells. TREM-1 expression was reduced with successful NB-UVB, etanercept and anti-IL-17 treatments. An in vitro model of PGN-activated monocytes as inflammatory myeloid DCs was developed to study TREM-1 blockade, and treatment with a TREM-1 blocking chimera decreased allogeneic Th17 activation, as well as IL-17 production. Furthermore, TREM-1 blockade of ex vivo psoriatic dendritic cells in an alloMLR also showed a decrease in IL-17. Together, these data suggest that the TREM-1 signaling pathway offers a novel therapeutic target to prevent the effects of inflammatory myeloid DCs in psoriasis. Overall design: Monocytes were isolated by plastic adherence, treated with TLR agonists overnight, washed twice and harvested in RTL-buffer. RNA was extracted and processed for microarray. 3 groups and 3 replicates with a paired structure across replicates

本课题组近期报道了一类在银屑病（psoriasis）发病机制中至关重要的抗原呈递细胞（antigen presenting cells），将其命名为炎性髓系树突状细胞（inflammatory myeloid dendritic cells，CD11c+ BDCA1-）。髓系细胞触发受体-1（Triggering receptor expressed on myeloid cells type-1，TREM-1）信号通路是该类细胞已发表转录组研究中的核心经典通路。TREM-1属于免疫球蛋白超家族（immunoglobulin superfamily），通过DAP12信号通路介导生物学活性，其天然配体目前仍未明确。经由TREM-1的激活可诱导IL-8、MCP/CCL2及TNF等多种炎性细胞因子的产生。
本研究进一步证实，TREM-1在健康个体与银屑病患者的皮肤组织中均有表达，且银屑病患者外周循环中的可溶性TREM-1水平显著升高。在银屑病皮损部位，TREM-1与树突状细胞及CD31+内皮细胞存在共定位现象。经窄谱中波紫外线（NB-UVB）、依那西普（etanercept）及抗IL-17疗法实现有效治疗后，皮损处TREM-1的表达水平可被显著下调。
本研究构建了肽聚糖（PGN）激活单核细胞以模拟炎性髓系树突状细胞的体外模型，用于开展TREM-1阻断策略的相关研究；实验结果显示，采用TREM-1阻断嵌合蛋白处理可抑制同种异体Th17细胞活化，并减少IL-17的分泌量。此外，在离体银屑病树突状细胞的同种异体混合淋巴细胞反应（alloMLR）体系中，阻断TREM-1同样可降低IL-17的产生水平。
综上，上述实验数据表明，TREM-1信号通路可为阻断银屑病中炎性髓系树突状细胞的致病效应提供全新的治疗靶点。
实验整体设计：通过塑料黏附法分离单核细胞，经Toll样受体（Toll-like receptor，TLR）激动剂过夜孵育后洗涤两次，以RTL缓冲液收集细胞。提取总RNA并进行微阵列芯片检测。实验设置3组处理，每组设3个生物学重复，重复样本间采用配对实验设计。