Cell:革兰氏阴性菌诱发炎症反应机制新解

7月20日，Cell杂志在线报道，革兰氏阴性菌感染通过TRIF信号途径激活NLRP3炎症小体，诱导炎症反应。

由于可引发"败血症综合征"，一种全身性难以控制的炎症反应，革兰氏阴性菌全身性感染以高死亡率著称。虽然大家公认革兰氏阴性细菌感染的免疫反应始于Toll样受体4对内毒素的识别，但革兰氏阴性菌血症过程中发生的炎症反应的分子机制仍不清楚。

本研究揭示了一个TRIF（含TIR结构域的诱导β-干扰素适配器，是一类可响应激活的Toll样受体的适配器）信号途径。所有革兰氏阴性菌均通过这一途径激活NLRP3炎症小体（NLRP3是PRR大家族中Nod样受体亚家族成员之一，在激活之后能够通过与接头蛋白相互作用，活化半胱氨酸蛋白酶-1（caspase-1），形成蛋白复合物"炎症小体"）。

通过TRIF，革兰氏阴性菌激活caspase-11。 TRIF通过I型干扰素的信号激活caspase-11，是caspase-11诱导和自我激活必要充分条件。 Caspase-11随后与组装好的NLRP3炎症小体协同调节caspase-1的激活，并导致不依赖于caspase-1的细胞死亡。这些事件尤其是发生在革兰氏阴性菌，而不是革兰氏阳性菌感染的情况下。

证实TRIF对caspase-11的调节作用突出表明，在革兰氏阴性细菌感染时，作为炎症小体的主要调节者，Toll样受体发挥重要作用。

doi:10.1016/j.cell.2011.10.017
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TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria

Vijay A.K. Rathinam, Sivapriya Kailasan Vanaja, Lisa Waggoner, Anna Sokolovska, Christine Becker, Lynda M. Stuart, John M. Leong, Katherine A. Fitzgerald

Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the sepsis syndrome, a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection.