NLRP3 inflammasome couples purinergic signaling with activation of the complement cascade for the optimal release of cells from bone marrow
NLRP3 inflammasome couples purinergic signaling with activation of the complement cascade for the optimal release of cells from bone marrow
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DOI：
10.1038/s41375-019-0436-6
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发表时间：
2019-04-01
期刊：
影响因子：
11.4
通讯作者：
Lenkiewicz, Anna M.
中科院分区：
文献类型：
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作者：
Ratajczak, Mariusz Z.;Adamiak, Mateusz;Lenkiewicz, Anna M.
调节造血干/祖细胞（HSPC）响应于应激、炎症、组织/器官损伤或动员诱导药物的施用而流出到外周血（PB）中的机制仍然没有很好地理解，并且由于干细胞运输在维持生物体内稳态中的重要性，认为涉及几种互补途径。我们的小组提出HSPC的动员主要是骨髓（BM）微环境中响应于促动员刺激的无菌炎症的结果，并且在动员过程的起始阶段，属于先天免疫系统的BM驻留细胞（包括粒细胞和单核细胞）释放与HSPC相关的分子模式分子DAMPs，也称为alarmins），活性氧（ROS），以及蛋白水解酶和脂肪分解酶。这些因素共同协调HSPC释放到PB中。在动员的起始阶段释放的最重要的DAMP之一是细胞外三磷酸腺苷，其是炎性小体的有效激活剂。作为其活化的结果，释放IL-1 β和IL-18以及其他促动员介质，包括DAMP如高分子组蛋白1（Hmgb 1）和S100钙结合蛋白A9（S100 a9）。这些DAMP是甘露聚糖结合凝集素（MBL）依赖性途径中补体级联（ComC）的重要激活剂。具体来说，Hmgb 1和S100 a9与MBL结合，从而导致MBL相关蛋白酶的激活，从而激活ComC，并同时触发凝血级联反应（CoaC）的激活。在这篇综述中，我们将突出的先天免疫细胞表达的NLRP 3炎性体，其中，在启动阶段的HSPC动员，夫妇嘌呤能信号与MBL依赖性途径的ComC，并在平行，CoaC的HSPC的最佳释放的新作用。这些数据对于优化HSPC的药理学动员是重要的。
The mechanisms that regulate egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) in response to stress, inflammation, tissue/organ injury, or administration of mobilization-inducing drugs are still not well understood, and because of the importance of stem cell trafficking in maintaining organism homeostasis, several complementary pathways are believed to be involved. Our group proposes that mobilization of HSPCs is mainly a result of sterile inflammation in the bone marrow (BM) microenvironment in response to pro-mobilizing stimuli and that during the initiation phase of the mobilization process BM-residing cells belonging to the innate immunity system, including granulocytes and monocytes, release danger-associated molecular pattern molecules (DAMPs, also known as alarmins), reactive oxygen species (ROS), as well as proteolytic and lipolytic enzymes. These factors together orchestrate the release of HSPCs into PB. One of the most important DAMPs released in the initiation phase of mobilization is extracellular adenosine triphosphate, a potent activator of the inflammasome. As a result of its activation, IL-1 beta and IL-18 as well as other promobilizing mediators, including DAMPs such as high molecular group box 1 (Hmgb1) and S100 calcium-binding protein A9 (S100a9), are released. These DAMPs are important activators of the complement cascade (ComC) in the mannanbinding lectin (MBL)-dependent pathway. Specifically, Hmgb1 and S100a9 bind to MBL, which leads to activation of MBL-associated proteases, which activate the ComC and in parallel also trigger activation of the coagulation cascade (CoaC). In this review, we will highlight the novel role of the innate immunity cell-expressed NLRP3 inflammasome, which, during the initiation phase of HSPC mobilization, couples purinergic signaling with the MBL-dependent pathway of the ComC and, in parallel, the CoaC for optimal release of HSPCs. These data are important to optimize the pharmacological mobilization of HSPCs.