Nrf2 down-regulation mediates pro-inflammatory effects of novel synthetic AhR ligands
2023
Authors:
Koprivica, IvanJonić, Natalija
Chatzigiannis, Christos
Tsiailanis, Antonis
Tzakos, Andreas G
Stojanović, Ivana D.
Document Type:
Conference object (Published version)
,
©2023 BenBedPhar Consortium
Metadata
Show full item recordAbstract:
Aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) are
transcription factors involved in the regulation of drug-metabolizing enzymes. Moreover,
both of them can modulate the immune response. AhR activation can lead to the activation
or inhibition of specific immune cells, especially at barrier tissues such as skin, lungs, gutassociated lymphoid tissue, etc. Nrf2 was also shown to play a role in the anti-inflammatory
process by inhibiting the recruitment of inflammatory cells and regulating anti-inflammatory
gene expression. Nrf2 gene transcription can be directly modulated by AhR activation, as
the Nrf2 promoter possesses three xenobiotic response element-like elements that were
shown to be able to bind AhR in response to a known Ahr agonist TCDD.
In this study, we explored the effect of newly synthetized AhR agonists (indole-based
derivatives) termed C46 and B19 on mouse macrophage differentiation. Peritoneal cells
were incubated with 1.5 µM of AhR ligands for 24 h, after which the proinflammatory M1
(F4/80+CD40+) and anti-inflammatory M2 (F4/80+CD206+) macrophage phenotype was
determined by flow cytometry. The results indicate that both compounds push
macrophages towards a more inflammatory state, as C46 tripled the M1/M2 ratio in culture,
while B19 doubled it, compared to the DMSO (0.005% v/v) control. Additionally, both
mRNA and protein expression of cytochrome P450 1A1 (CYP1A1), commonly used as an
indicator of AhR activation, were also increased by C46 and B19. Finally, western blot
analysis showed that both of the tested AhR ligands downregulated the protein expression
of Nrf2 within the treated cells.
These results suggest that AhR activation and subsequent Nrf2 down-regulation by the
newly synthesized AhR agonists C46 and B19 boosted the proinflammatory phenotype of
mouse peritoneal macrophages.
Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
In:
- 5th Scientific Meeting of the COST Action CA20121: Bench to Bedside Transition for Pharmacological Regulation of NRF2 in non-communicable diseases (BenBedPhar): Translating NRF2 Research into Clinical Practice; 2023 Oct 12-13; Graz, Austria. BenBedPhar Consortium, 2023. p. 38.