Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia
Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia
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DOI：
10.4049/jimmunol.178.5.3153
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Worthen, G. Scott
中科院分区：
文献类型：
--
作者：
Jeyaseelan, Samithamby;Young, Scott K.;Worthen, G. Scott
细菌性肺炎仍然是一种严重的疾病，与中性粒细胞募集有关。先天免疫是消除细菌的关键，TLR在这个过程中是必不可少的。含有Toll/IL-1 R结构域的衔接子诱导IFN-β（TRIF）是TLR 3和TLR 4的衔接子，与MyD 88非依赖性级联反应相关。然而，TRIF在针对肺部细菌病原体的免疫应答中的重要性尚未得到很好的理解。我们研究了TRIF在大肠杆菌肺炎小鼠模型中的参与。TRIF-/-小鼠感染E.大肠杆菌显示减弱的中性粒细胞迁移; NF-κ B活化;以及TNF-α、IL-6和LPS诱导的肺中C-X-C趋化因子产生。此外，E.在TRIF+/+小鼠的骨髓源性巨噬细胞（BMPs）中检测到大肠杆菌诱导的JNK、ERK和p38 MAPK磷酸化，但在TRIF-/-小鼠的BMPs中减弱。此外，还发现E.大肠杆菌诱导的TNF-α和IL-6的产生在TRIF-/-小鼠的BCLF中减弱。E. coli LPS诱导的晚期MAPK活化，以及TRIF-/-小鼠的BMPs中TNF-α和IL-6的产生被消除。此外，TRIF不是肺中LPS诱导的中性粒细胞流入和角质形成细胞衍生的趋化因子MIP-2和LPS诱导的C-X-C趋化因子产生所必需的。使用TLR 3（-/-）小鼠，我们排除了TLR 3介导的TRIF依赖性中性粒细胞内流在E.大肠杆菌肺炎。TLR 4阻断Ab抑制E.大肠杆菌诱导的TNF-α和IL-6在TRIF-/-和TRIF+/+小鼠的BCR 4中的表达，表明TRIF介导的信号传导涉及TLR 4。我们还发现TRIF对控制E.肺内大肠杆菌负荷和E.大肠杆菌播散。因此，TRIF依赖性TLR 4介导的信号级联反应的快速激活有助于增强肺宿主对革兰氏阴性病原体的防御。
Bacterial pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia coli pneumonia. TRIF-/- mice infected with E. coli display attenuated neutrophil migration; NF-kappa B activation; and TNF-alpha, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. coli-induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF+/+ mice, but attenuated in BMMs of TRIF-/- mice. Furthermore, E. coli-induced TNF-alpha and IL-6 production was attenuated in BMMs of TRIF-/- mice. E. coli LPS-induced late MAPK activation, and TNF-alpha and IL-6 production were abolished in BMMs of TRIF-/- mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3(-/-) mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. coli pneumonia. A TLR4-blocking Ab inhibited E. coli-induced TNF-alpha and IL-6 in BMMs of both TRIF-/- and TRIF+/+ mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. coli burden in the lungs and E. coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.