Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection.
Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection.
复制标题
DOI：
10.4049/immunohorizons.1900004
复制
发表时间：
2019-06-17
期刊：
影响因子：
--
通讯作者：
Lawrence, B Paige
中科院分区：
文献类型：
--
作者：
Franchini, Anthony M;Myers, Jason R;Lawrence, B Paige
在原发性甲型流感病毒感染期间，配体诱导型芳烃受体 (AhR) 的激活通过负向调节树突状细胞 (DC) 启动幼稚 CD8+ T 细胞的能力来减弱宿主反应，从而减少 CTL 的产生。然而，DC 中 AhR 调控的基因和信号通路尚不完全清楚。在这项研究中，我们使用无偏基因表达谱来识别 DC 中受体内 AhR 激活调节的差异表达基因和信号通路。使用原型 AhR 激动剂 TCDD，我们确定了凝集素受体 Cd209a (DC-SIGN) 和趋化因子 Ccl17 作为新的 AhR 靶基因。我们进一步表明，感染期间 AhR 激活显着降低了表面表达 CD209a 的 DC 的百分比。尽管甲型流感病毒感染增加了肺和肺引流淋巴结中的 CCL17 蛋白水平，但在 AhR 激活后，该蛋白水平显着降低。造血室中 AhR 的靶向切除证实了 AhR 是下调 CCL17 和 CD209a 所必需的。 AhR 功能性 DNA 结合域的丢失表明，单独的 AhR 激活是必要的，但不足以驱动下调。 AhR 激活在人单核细胞衍生的 DC 中诱导了类似的基因表达变化。对小鼠和人类 Cd209a 和 Ccl17 上游调控区的分析揭示了 AhR 的一组潜在转录因子伙伴，它们可能在体内共同调控这些基因。这项研究强调了 DC 内 AhR 调节途径的广度，并且 AhR 可能与其他转录因子相互作用以在感染期间调节 DC 功能。
Activation of the ligand inducible aryl hydrocarbon receptor (AhR) during primary influenza A virus infection diminishes host responses by negatively regulating the ability of dendritic cells (DC) to prime naive CD8+ T cells, which reduces the generation of CTL. However, AhR-regulated genes and signaling pathways in DCs are not fully known. In this study, we used unbiased gene expression profiling to identify differentially expressed genes and signaling pathways in DCs that are modulated by AhR activation in vivo. Using the prototype AhR agonist TCDD, we identified the lectin receptor Cd209a (DC-SIGN) and chemokine Ccl17 as novel AhR target genes. We further show the percentage of DCs expressing CD209a on their surface was significantly decreased by AhR activation during infection. Whereas influenza A virus infection increased CCL17 protein levels in the lung and lung-draining lymph nodes, this was significantly reduced following AhR activation. Targeted excision of AhR in the hematopoietic compartment confirmed AhR is required for downregulation of CCL17 and CD209a. Loss of AhR's functional DNA-binding domain demonstrates that AhR activation alone is necessary but not sufficient to drive downregulation. AhR activation induced similar changes in gene expression in human monocyte-derived DCs. Analysis of the murine and human upstream regulatory regions of Cd209a and Ccl17 revealed a suite of potential transcription factor partners for AhR, which may coregulate these genes in vivo. This study highlights the breadth of AhR-regulated pathways within DCs, and that AhR likely interacts with other transcription factors to modulate DC functions during infection.