Punicalagin as a novel selective aryl hydrocarbon receptor (AhR) modulator upregulates AhR expression through the PDK1/p90RSK/AP-1 pathway to promote the anti-inflammatory response and bactericidal activity of macrophages.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Weihong Dai, Shuangqin Yin, Fangjie Wang, Tianyin Kuang, Hongyan Xiao, Wenyuan Kang, Caihong Yun, Fei Wang, Li Luo, Shengxiang Ao, Jing Zhou, Xue Yang, Chao Fan, Wei Li, Dongmei He, He Jin, Wanqi Tang, Lizhu Liu, Rixing Wang, Huaping Liang, Junyu Zhu
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Abstract

Aryl hydrocarbon receptor (AhR) plays an important role in inflammation and immunity as a new therapeutic target for infectious disease and sepsis. Punicalagin (PUN) is a Chinese herbal monomer extract of pomegranate peel that has beneficial anti-inflammatory, antioxidant and anti-infective effects. However, whether PUN is a ligand of AhR, its effect on AhR expression, and its signaling pathway remain poorly understood. In this study, we found that PUN was a unique polyphenolic compound that upregulated AhR expression at the transcriptional level, and regulated the AhR nongenomic pathway. AhR expression in lipopolysaccharide-induced macrophages was upregulated by PUN in vitro and in vivo in a time- and dose-dependent manner. Using specific inhibitors and siRNA, induction of AhR by PUN depended on sequential phosphorylation of 90-kDa ribosomal S6 kinase (p90RSK), which was activated by the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide-dependent protein kinase (PDK)1 pathways. PUN promoted p90RSK-mediated activator protein-1 (AP-1) activation. AhR knockout or inhibitors reversed suppression of interleukin (IL)-6 and IL-1β expression by PUN. PUN decreased Listeria load and increased macrophage survival via AhR upregulation. In conclusion, we identified PUN as a novel selective AhR modulator involved in AhR expression via the MEK/ERK and PDK1 pathways targeting p90RSK/AP-1 in inflammatory macrophages, which inhibited macrophage inflammation and promoted bactericidal activity.

Punicalagin 作为一种新型选择性芳基烃受体(AhR)调节剂,可通过 PDK1/p90RSK/AP-1 途径上调 AhR 的表达,从而促进巨噬细胞的抗炎反应和杀菌活性。
芳基烃受体(AhR)在炎症和免疫中发挥着重要作用,是治疗感染性疾病和败血症的新靶点。Punicalagin(PUN)是石榴皮的一种中药单体提取物,具有抗炎、抗氧化和抗感染的功效。然而,人们对 PUN 是否是 AhR 的配体、其对 AhR 表达的影响及其信号传导途径仍知之甚少。本研究发现,PUN 是一种独特的多酚类化合物,它能在转录水平上调 AhR 的表达,并调节 AhR 非基因组通路。在体外和体内,脂多糖诱导的巨噬细胞中的 AhR 表达均受 PUN 的调控,且具有时间和剂量依赖性。利用特异性抑制剂和 siRNA,PUN 对 AhR 的诱导依赖于 90-kDa 核糖体 S6 激酶(p90RSK)的连续磷酸化,该激酶由丝裂原活化蛋白激酶激酶(MEK)/细胞外信号调节激酶(ERK)和磷酸肌醇依赖性蛋白激酶(PDK)1 途径激活。PUN 促进了 p90RSK 介导的活化蛋白-1(AP-1)激活。AhR基因敲除或抑制剂逆转了PUN对白细胞介素(IL)-6和IL-1β表达的抑制。PUN通过上调AhR降低了李斯特菌的负荷并提高了巨噬细胞的存活率。总之,我们发现PUN是一种新型的选择性AhR调节剂,它通过MEK/ERK和PDK1途径参与炎性巨噬细胞中p90RSK/AP-1的AhR表达,从而抑制巨噬细胞炎症并促进杀菌活性。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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