7月20日,，Cell雜志在線報道,，革蘭氏陰性菌感染通過TRIF信號途徑激活NLRP3炎癥小體，誘導炎癥反應,。
由于可引發(fā)"敗血癥綜合征",，一種全身性難以控制的炎癥反應，革蘭氏陰性菌全身性感染以高死亡率著稱,。雖然大家公認革蘭氏陰性細菌感染的免疫反應始于Toll樣受體4對內(nèi)毒素的識別,，但革蘭氏陰性菌血癥過程中發(fā)生的炎癥反應的分子機制仍不清楚。
本研究揭示了一個TRIF（含TIR結(jié)構(gòu)域的誘導β-干擾素適配器,，是一類可響應激活的Toll樣受體的適配器）信號途徑,。所有革蘭氏陰性菌均通過這一途徑激活NLRP3炎癥小體（NLRP3是PRR大家族中Nod樣受體亞家族成員之一，在激活之后能夠通過與接頭蛋白相互作用,，活化半胱氨酸蛋白酶-1（caspase-1）,，形成蛋白復合物"炎癥小體"）。
通過TRIF,，革蘭氏陰性菌激活caspase-11,。 TRIF通過I型干擾素的信號激活caspase-11，是caspase-11誘導和自我激活必要充分條件,。 Caspase-11隨后與組裝好的NLRP3炎癥小體協(xié)同調(diào)節(jié)caspase-1的激活,，并導致不依賴于caspase-1的細胞死亡。這些事件尤其是發(fā)生在革蘭氏陰性菌,，而不是革蘭氏陽性菌感染的情況下,。
證實TRIF對caspase-11的調(diào)節(jié)作用突出表明，在革蘭氏陰性細菌感染時,，作為炎癥小體的主要調(diào)節(jié)者,，Toll樣受體發(fā)揮重要作用。（生物谷bioon.com）
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.
