Peres Adam G, Zamboni Robert, King Irah L, Madrenas Joaquín
Department of Microbiology and Immunology, Microbiome and Disease Tolerance Centre, McGill University, Montréal, Quebec, Canada.
Department of Chemistry, McGill University, Montréal, Quebec, Canada; and.
J Leukoc Biol. 2017 Dec;102(6):1471-1480. doi: 10.1189/jlb.4A0617-218RR. Epub 2017 Oct 10.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that triggers a broad response, which includes the regulation of proinflammatory cytokine production by monocytes and macrophages. AHR is negatively regulated by a set of genes that it transcriptionally activates, including the AHR repressor () and the cytochrome P450 1 () family, which are critical for preventing exacerbated AHR activity. An imbalance in these regulatory mechanisms has been shown to cause severe defects in lymphoid cells. Therefore, we wanted to assess how AHR activation is regulated in monocytes and macrophages in the context of innate immune responses induced by pathogen-associated molecular patterns (PAMPs). We found that concomitant stimulation of primary human monocytes with PAMPs and the AHR agonist 6-formylindolo(3,2-b)carbazole (FICZ) led to a selective dose-dependent inhibition of family members induction. Two other AHR-dependent genes [ and NADPH quinone dehydrogenase 1 ()] were not affected under these conditions, suggesting a split in the AHR regulation by PAMPs. This down-regulation of family members did not require de novo protein production nor signaling through p38, ERK, or PI3K-Akt-mammalian target of rapamycin (mTOR) pathways. Furthermore, such a split regulation of the AHR response was more apparent in GM-CSF-derived macrophages, a finding corroborated at the functional level by decreased CYP1 activity and decreased proinflammatory cytokine production in response to FICZ and LPS. Collectively, our findings identify a role for pattern recognition receptor (PRR) signaling in regulating the AHR response through selective down-regulation of expression in human monocytes and macrophages.
芳烃受体（AHR）是一种配体激活的转录因子，可引发广泛的反应，包括调节单核细胞和巨噬细胞促炎细胞因子的产生。AHR受到一组由其转录激活的基因的负调控，包括AHR阻遏物（AHRR）和细胞色素P450 1（CYP1）家族，它们对于防止AHR活性加剧至关重要。这些调节机制的失衡已被证明会导致淋巴细胞出现严重缺陷。因此，我们想评估在病原体相关分子模式（PAMP）诱导的先天免疫反应背景下，单核细胞和巨噬细胞中AHR激活是如何被调节的。我们发现，用PAMP和AHR激动剂6-甲酰基吲哚并（3,2-b）咔唑（FICZ）同时刺激原代人单核细胞会导致对CYP1家族成员诱导的选择性剂量依赖性抑制。在这些条件下，另外两个AHR依赖性基因[芳烃羟化酶（AHH）和NADPH醌脱氢酶1（NQO1）]不受影响，这表明PAMP对AHR的调节存在分歧。CYP1家族成员的这种下调既不需要从头合成蛋白质，也不需要通过p38、细胞外信号调节激酶（ERK）或磷脂酰肌醇-3激酶-蛋白激酶B-雷帕霉素哺乳动物靶蛋白（PI3K-Akt-mTOR）途径进行信号传导。此外，AHR反应的这种分裂调节在粒细胞-巨噬细胞集落刺激因子（GM-CSF）衍生的巨噬细胞中更为明显，这一发现通过CYP1活性降低以及对FICZ和脂多糖（LPS）反应时促炎细胞因子产生减少在功能水平上得到了证实。总的来说，我们的研究结果确定了模式识别受体（PRR）信号传导在通过选择性下调人单核细胞和巨噬细胞中CYP1表达来调节AHR反应中的作用。
