III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Immunobiology. 2013 Apr;218(4):664-73. doi: 10.1016/j.imbio.2012.07.029. Epub 2012 Aug 7.
The success of a vaccine consists in the induction of an innate immune response and subsequent activation of the adaptive immune system. Because antigens are usually not immunogenic, the addition of adjuvants that activate innate immunity is required. The mycobacterial cord factor trehalose-6,6'-dimycolate (TDM) and its synthetic adjuvant analogue trehalose-6,6'-dibehenate (TDB) rely on the C-type lectin Mincle and the signaling molecules Syk and Card9 to trigger innate immunity. In this study, we show that stimulation of bone marrow-derived dendritic cells (BMDCs) with TDB induces Nlrp3 inflammasome-dependent IL-1β secretion. While Card9 is required for NF-κB activation by TDB, it is dispensable for TDB-induced activation of the Nlrp3 inflammasome. Additionally, efflux of intracellular potassium, lysosomal rupture, and oxygen radical (ROS) production are crucial for caspase-1 processing and IL-1β secretion by TDB. In an in vivo inflammation model, we demonstrate that the recruitment of neutrophils by TDB is significantly reduced in the Nlrp3-deficient mice compared to the wild-type mice, while the production of chemokines in vitro is not influenced by the absence of Nlrp3. These results identify the Nlrp3 inflammasome as an essential mediator for the induction of an innate immune response triggered by TDB.
疫苗的成功在于诱导先天免疫反应和随后激活适应性免疫系统。因为抗原通常没有免疫原性，所以需要添加激活先天免疫的佐剂。分枝杆菌 cord 因子海藻糖-6,6'-二(mycolic)酸 (TDM)及其合成佐剂类似物海藻糖-6,6'-二(二十二酸) (TDB)依赖于 C 型凝集素 Mincle 和信号分子 Syk 和 Card9 来触发先天免疫。在这项研究中，我们表明 TDB 刺激骨髓来源的树突状细胞 (BMDC) 会诱导 Nlrp3 炎性体依赖性的 IL-1β 分泌。虽然 Card9 是 TDB 激活 NF-κB 所必需的，但它对于 TDB 诱导的 Nlrp3 炎性体的激活是可有可无的。此外，细胞内钾的外排、溶酶体破裂和氧自由基 (ROS) 的产生对于 TDB 诱导的 caspase-1 加工和 IL-1β 分泌至关重要。在体内炎症模型中，我们证明与野生型小鼠相比，TDB 招募中性粒细胞在 Nlrp3 缺陷型小鼠中显著减少，而 Nlrp3 缺失并不影响体外趋化因子的产生。这些结果表明 Nlrp3 炎性体是 TDB 触发的先天免疫反应诱导的必需介质。
