Ramana Chilakamarti V, Cheng Guang-Shing, Kumar Aseem, Kwon Hyung-Joo, Enelow Richard I
Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
Mol Immunol. 2009 Dec;47(2-3):623-31. doi: 10.1016/j.molimm.2009.09.001. Epub 2009 Sep 27.
Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8(+) T cells in this injury, and have found that the critical effector molecule is TNF-alpha expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen-specific CD8(+) T cell recognition, and demonstrate that the early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF-alpha-dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection.
远端气道的流感感染会导致严重的肺损伤，其中相当一部分是免疫病理损伤，归因于宿主反应。我们使用小鼠模型专门研究了抗病毒CD8(+) T细胞在这种损伤中的作用，发现关键的效应分子是T细胞在识别抗原后表达的肿瘤坏死因子-α（TNF-α）。有趣的是，随后发生的免疫病理特征是宿主炎症细胞大量积聚，这些细胞是由靶肺泡上皮细胞表达的趋化因子招募而来的。在本研究中，我们分析了抗原特异性CD8(+) T细胞识别引发上皮趋化因子表达的诱导机制，证明早期生长反应因子-1（Egr-1）转录因子在体外和体内上皮细胞中均被快速诱导表达，并且它是许多炎症趋化因子的关键调节因子。Egr-1基因缺陷显著消除了与T细胞识别相关的趋化因子表达和免疫病理损伤，并且它直接调节典型CXC趋化因子MIP-2的转录活性。我们进一步证明，Egr-1的诱导是由TNF-α依赖的细胞外信号调节激酶（ERK）激活触发的抑制该途径会消除Egr-1的表达。这些发现表明，Egr-1可能是减轻严重流感感染免疫病理的一个重要靶点。
