Inactivation of DAP12 in PMN Inhibits TREM1-Mediated Activation in Rheumatoid Arthritis
Inactivation of DAP12 in PMN Inhibits TREM1-Mediated Activation in Rheumatoid Arthritis
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DOI：
10.1371/journal.pone.0115116
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发表时间：
2015-02-02
期刊：
影响因子：
3.7
通讯作者：
Wei, Sheng
中科院分区：
文献类型：
--
作者：
Chen, Xianghong;Eksioglu, Erika A.;Wei, Sheng
类风湿性关节炎（RA）是一种自身免疫性疾病，其特征在于影响滑膜、骨和软骨的失调和慢性全身性炎症反应，导致关节外组织损伤。先天免疫是抵抗入侵病原体的第一道防线，并协助启动适应性免疫应答。包括嗜中性粒细胞在内的多形核细胞（PMN）是外周血中最大的白色血细胞群体，并且通过吞噬作用、细胞因子产生和天然的细胞因子样细胞毒性活性在功能上产生其炎症作用。TREM 1（髓样细胞表达的触发受体）是PMN中的炎性受体，其通过使用细胞内活化衔接子DAP 12来诱导下游信号传导而发出信号。TREM交联后，DAP 12的ITAM基序中的酪氨酸被磷酸化，诱导Syk酪氨酸激酶的募集并最终激活PI 3激酶和ERK信号通路。虽然TREM 1和DAP 12都已被证明是RA发病机制的重要激活剂，但它们在PMN中的活性或DAP 12作为可能的治疗靶点的重要性尚未显示。在这里，我们证实，使用原发性RA标本，分离的中性粒细胞有一个增加的比例相比，正常的健康对照分离的中性粒细胞在蛋白质和基因表达水平的TREM 1和DAP 12。这种增加的表达与ERK和MAPK的活化、IL-8和RANTES的分泌以及靶细胞的细胞毒性的增加高度相关。重要的是，基于我们的假设，激活和抑制信号在RA的发病机制的不平衡，我们证明，抑制DAP 12信号通路灭活这些重要的炎症细胞。
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.