Manuka Honey activates the Aryl Hydrocarbon Receptor: implications for skin inflammation.
Manuka Honey activates the Aryl Hydrocarbon Receptor: implications for skin inflammation.
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DOI：
10.1016/j.phrs.2023.106848
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发表时间：
2023-07
影响因子：
9.3
通讯作者：
A. Alangari;M. D. Ashoori;W. Alwan;H. Dawe;B. Stockinger;J. Barker;E. Wincent;P. Di Meglio
中科院分区：
文献类型：
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作者：
A. Alangari;M. D. Ashoori;W. Alwan;H. Dawe;B. Stockinger;J. Barker;E. Wincent;P. Di Meglio
麦卢卡蜂蜜(MH)是一种具有抗菌、抗氧化和抗炎活性的复合营养物质。我们先前已经证明MH下调IL-4诱导的永生化角质形成细胞中CCL26的表达。由于MH含有潜在的芳香烃受体(AHR)的配体，AHR是皮肤动态平衡的关键调节因子，我们假设这种作用是通过AHR激活来调节的。在这里，我们处理了稳定转染空载体的HaCaT细胞(EV-HaCaT)或稳定沉默AHR的HaCaT细胞(AHR沉默的HaCaT)；或者用2%的MH处理原代正常人角质形成细胞(NHEK)24小时。这导致EV-HaCaT细胞的CYP1A1上调15.4倍，而在AHR沉默的细胞中这一上调显著降低。AHR拮抗剂CH223191可完全阻断这一作用。在Nhek也观察到了类似的发现。与凡士林相比，Cyp1a1Crex R26ReYFP报告品系小鼠皮肤用纯MH体内处理后显著诱导了CYP1A1的表达。用2%MH处理HaCaT后3h和6h酶活性显著降低，12h后酶活性升高，提示MH可能通过直接和间接途径激活AHR。重要的是，在AHR沉默的HaCaT中，MH对IL-4诱导的CCL26 mRNA和蛋白的下调被取消，并被CH223191预先处理。最后，MH以AHR依赖的方式显著上调NHEK中FLG的表达。综上所述，MH在体外和体内均能激活AHR，从而为其诱导CCL26下调和上调FLG的表达提供了一种机制。这些结果对特应性疾病和其他疾病具有潜在的临床意义。
Manuka honey (MH) is a complex nutritional material with antimicrobial, antioxidant and anti-inflammatory activity. We have previously shown that MH down regulates IL-4-induced CCL26 expression in immortalized keratinocytes. As MH contains potential ligands of the Aryl Hydrocarbon Receptor (AHR), a key regulator of skin homeostasis, we hypothesize that this effect is mediatedviaAHR activation. Here, we treated HaCaT cell lines, either stable transfected with an empty vector (EV-HaCaT) or in which AHR had been stable silenced (AHR-silenced HaCaT); or primary normal human epithelial keratinocytes (NHEK) with 2% MH for 24 h. This induced a 15.4-fold upregulation ofCYP1A1in EV-HaCaTs, which was significantly reduced in AHR-silenced cells. Pre-treatment with the AHR antagonist CH223191 completely abrogated this effect. Similar findings were observed in NHEK. In vivo treatment of the Cyp1a1Crex R26ReYFPreporter mice strain’s skin with pure MH significantly induced CYP1A1 expression compared with Vaseline. Treatment of HaCaT with 2% MH significantly decreased baseline CYP1 enzymatic activity at 3 and 6 h but increased it after 12 h, suggesting that MH may activate the AHR both through direct and indirect means. Importantly, MH downregulation of IL-4-induced CCL26 mRNA and protein was abrogated in AHR-silenced HaCaTs and by pre-treatment with CH223191. Finally, MH significantly upregulatedFLGexpression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, bothin vitroandin vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation ofFLGexpression. These results have potential clinical implications for atopic diseases and beyond.