TY - JOUR
T1 - Manuka honey activates the Aryl Hydrocarbon receptor
T2 - implications for skin inflammation
AU - Alangari, Abdullah A.
AU - Ashoori, Matin D.
AU - Alwan, Wisam
AU - Dawe, Hannah
AU - Stockinger, Brigitta
AU - Barker, Jonathan N.
AU - Wincent, Emma
AU - Di Meglio, Paola
N1 - Funding Information:
This study was funded by the Deanship of Scientific Research at King Saud University through the research group project No. RGP-190 (to A.A.A), a National Psoriasis Foundation Translational Award 814364 (to P.D.M.), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London (to J.B. and P.D.M), the Medical Research Council/British Association of Dermatologists/British Skin Foundation for a Clinical Research Fellowship No. MR/P001394/1 (to W.A), the Swedish Research Council (VR) grant No. 2020-03418 (to E.W), and by a Wellcome Trust Grant 210556/Z/18/Z (to B.S). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or other funding bodies. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding Information:
This study was funded by the Deanship of Scientific Research at King Saud University through the research group project No. RGP-190 (to A.A.A), a National Psoriasis Foundation Translational Award 814364 (to P.D.M.), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London (to J.B. and P.D.M), the Medical Research Council/British Association of Dermatologists/British Skin Foundation for a Clinical Research Fellowship No. MR/P001394/1 (to W.A), the Swedish Research Council (VR) grant No. 2020-03418 (to E.W), and by a Wellcome Trust Grant 210556/Z/18/Z (to B.S). . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or other funding bodies. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - 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 mediated via AHR 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 of CYP1A1 in 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 Cyp1a1Cre x R26ReYFP reporter 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 upregulated FLG expression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, both in vitro and in vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation of FLG expression. These results have potential clinical implications for atopic diseases and beyond.
AB - 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 mediated via AHR 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 of CYP1A1 in 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 Cyp1a1Cre x R26ReYFP reporter 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 upregulated FLG expression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, both in vitro and in vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation of FLG expression. These results have potential clinical implications for atopic diseases and beyond.
UR - https://www.scopus.com/pages/publications/85164336034
U2 - 10.1016/j.phrs.2023.106848
DO - 10.1016/j.phrs.2023.106848
M3 - Article
SN - 1043-6618
VL - 194
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106848
ER -