Department of Microbiology and Immunology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD, USA.
Department of Genetics, UNC School of Medicine, Chapel Hill, NC, USA.
Nat Immunol. 2018 Dec;19(12):1309-1318. doi: 10.1038/s41590-018-0243-7. Epub 2018 Nov 5.
The unique cell biology of Toll-like receptor 4 (TLR4) allows it to initiate two signal-transduction cascades: a signal dependent on the adaptors TIRAP (Mal) and MyD88 that begins at the cell surface and regulates proinflammatory cytokines, and a signal dependent on the adaptors TRAM and TRIF that begins in the endosomes and drives the production of type I interferons. Negative feedback circuits to limit TLR4 signals from both locations are necessary to balance the inflammatory response. We describe a negative feedback loop driven by autocrine-paracrine prostaglandin E (PGE) and the PGE receptor EP4 that restricted TRIF-dependent signals and the induction of interferon-β through the regulation of TLR4 trafficking. Inhibition of PGE production or antagonism of EP4 increased the rate at which TLR4 translocated to endosomes and amplified TRIF-dependent activation of the transcription factor IRF3 and caspase-8. This PGE-driven mechanism restricted TLR4-TRIF signaling in vitro after infection of macrophages by the Gram-negative pathogens Escherichia coli or Citrobacter rodentium and protected mice against mortality induced by Salmonella enteritidis serovar Typhimurium. Thus, PGE restricted TLR4-TRIF signaling specifically in response to lipopolysaccharide.
Toll 样受体 4（TLR4）独特的细胞生物学特性使其能够启动两条信号转导级联反应：一条信号通路依赖于衔接蛋白 TIRAP（Mal）和 MyD88，该通路起始于细胞表面并调节促炎细胞因子的产生；另一条信号通路依赖于衔接蛋白 TRAM 和 TRIF，该通路起始于内体并驱动 I 型干扰素的产生。为了平衡炎症反应，需要从这两个位置建立负反馈回路来限制 TLR4 信号。我们描述了一个由自分泌旁分泌前列腺素 E（PGE）和 PGE 受体 EP4 驱动的负反馈回路，该回路通过调节 TLR4 的运输来限制 TRIF 依赖性信号和干扰素-β的诱导。抑制 PGE 的产生或拮抗 EP4 增加了 TLR4 向内体易位的速度，并放大了 TRIF 依赖性转录因子 IRF3 和半胱天冬酶-8 的激活。在革兰氏阴性病原体大肠杆菌或鼠柠檬酸杆菌感染巨噬细胞后，这种 PGE 驱动的机制在体外限制了 TLR4-TRIF 信号，并且保护了小鼠免受肠炎沙门氏菌血清型 Typhimurium 诱导的死亡率。因此，PGE 特异性地限制了 TLR4-TRIF 信号，以响应脂多糖。
