Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
J Exp Med. 2011 Dec 19;208(13):2705-16. doi: 10.1084/jem.20110547. Epub 2011 Nov 28.
Toll-like receptor 4 (TLR4), which signals through the adapter molecules myeloid differentiation factor 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter inducing IFN-β (TRIF), is required for protection against Gram-negative bacteria. TRIF is known to be important in TLR3-mediated antiviral signaling, but the role of TRIF signaling against Gram-negative enteropathogens is currently unknown. We show that TRIF signaling is indispensable for establishing innate protective immunity against Gram-negative Yersinia enterocolitica. Infection of wild-type mice rapidly induced both IFN-β and IFN-γ in the mesenteric lymph nodes. In contrast, TRIF-deficient mice were defective in these IFN responses and showed impaired phagocytosis in regional macrophages, resulting in greater bacterial dissemination and mortality. TRIF signaling may be universally important for protection against Gram-negative pathogens, as TRIF-deficient macrophages were also impaired in killing both Salmonella and Escherichia coli in vitro. The mechanism of TRIF-mediated protective immunity appears to be orchestrated by macrophage-induced IFN-β and NK cell production of IFN-γ. Sequential induction of IFN-β and IFN-γ leads to amplification of macrophage bactericidal activity sufficient to eliminate the invading pathogens at the intestinal interface. Our results demonstrate a previously unknown role of TRIF in host resistance to Gram-negative enteropathogens, which may lead to effective strategies for combating enteric infections.
Toll 样受体 4（TLR4）通过衔接分子髓样分化因子 88（MyD88）和 Toll/白细胞介素 1 受体结构域包含衔接诱导 IFN-β（TRIF）发出信号，是抵抗革兰氏阴性菌所必需的。TRIF 已知在 TLR3 介导的抗病毒信号中很重要，但 TRIF 信号对革兰氏阴性肠病原体的作用目前尚不清楚。我们发现 TRIF 信号对于建立针对革兰氏阴性耶尔森氏菌的先天保护性免疫是必不可少的。野生型小鼠的感染迅速在肠系膜淋巴结中诱导 IFN-β 和 IFN-γ 的产生。相比之下，TRIF 缺陷型小鼠在这些 IFN 反应中存在缺陷，并且区域巨噬细胞中的吞噬作用受损，导致细菌播散和死亡率增加。TRIF 信号可能对抵抗革兰氏阴性病原体普遍重要，因为 TRIF 缺陷型巨噬细胞在体外也不能杀死沙门氏菌和大肠杆菌。TRIF 介导的保护性免疫的机制似乎是由巨噬细胞诱导的 IFN-β 和 NK 细胞产生 IFN-γ 协调的。IFN-β 和 IFN-γ 的顺序诱导导致巨噬细胞杀菌活性的放大，足以在肠内界面消除入侵的病原体。我们的结果表明 TRIF 在宿主抵抗革兰氏阴性肠病原体方面具有先前未知的作用，这可能为对抗肠道感染提供有效的策略。
