Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection with Salmonella and many other pathogens, flagellin is a major activator of NLRC4 inflammasome-mediated macrophage pyroptosis and pathogen eradication. Salmonella switches to a flagellin-low phenotype as infection progresses to avoid this mechanism of clearance by the host. However, the host cues that Salmonella perceives to undergo this switch remain unclear. Here, we report an unexpected role of the NLRC4 inflammasome in promoting expression of its microbial ligand, flagellin, and identify a role for type 1 IFN signaling in switching of Salmonella to a flagellin-low phenotype. Early in infection, activation of NLRC4 by flagellin initiates pyroptosis and concomitant release of lysophospholipids which in turn enhance expression of flagellin by Salmonella thereby amplifying its ability to elicit cell death. TRIF-dependent production of type 1 IFN, however, later represses NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2, causing a decline in intracellular lysophospholipids that results in down-regulation of flagellin expression by Salmonella. These findings reveal a previously unrecognized immune-modulating regulatory cross-talk between endosomal TLR signaling and cytosolic NLR activation with significant implications for the establishment of infection with Salmonella.

炎症小体与多种细菌病原体的检测和清除有关，但人们对这种先天传感机制是否对病原体刺激配体的表达具有任何调节作用知之甚少。在沙门氏菌和许多其他病原体感染期间，鞭毛蛋白是 NLRC4 炎性体介导的巨噬细胞焦亡和病原体根除的主要激活剂。随着感染的进展，沙门氏菌会转变为低鞭毛蛋白表型，以避免宿主的这种清除机制。然而，沙门氏菌认为经历这种转变的宿主线索仍不清楚。在这里，我们报告了 NLRC4 炎症小体在促进其微生物配体鞭毛蛋白表达方面的意外作用，并确定了 1 型 IFN 信号传导在沙门氏菌向鞭毛蛋白低表型转变中的作用。在感染早期，鞭毛蛋白激活 NLRC4 会引发细胞焦亡并伴随溶血磷脂的释放，从而增强沙门氏菌鞭毛蛋白的表达，从而增强其引发细胞死亡的能力。然而，TRIF 依赖性 1 型 IFN 的产生随后会抑制 NLRC4 和溶血磷脂生物合成酶 iPLA2，导致细胞内溶血磷脂下降，从而导致沙门氏菌鞭毛蛋白表达下调。这些发现揭示了内体 TLR 信号传导和胞质 NLR 激活之间以前未被认识的免疫调节调节串扰，对沙门氏菌感染的建立具有重要意义。