Abstract
Sensing microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Nevertheless, the involved cellular processes triggered by the metabolites are mainly unknown. Here, we analyzed proteomic changes in macrophages after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic exogenous AhR-ligand benzo(a)pyrene (BaP) in the absence and presence of lipopolysaccharide (LPS) to identify affected cellular processes and pathways. The AhR-ligands regulated metabolic and immunologic processes in dependency of LPS co-stimulation. All investigated ligands time-dependently enhanced fatty acid β-oxidation. Differences due to the combination with LPS were observed for all three ligands. Additionally, oxidative phosphorylation was significantly increased by IAld and I3AA in a time and LPS-dependent manner. Immunoregulatory processes were affected in distinct ways. While BaP and I3AA up-regulated IL-8 signaling, IL-6 signaling was decreased by IAld. BaP decreased the inflammasome pathway. Thus, AhR-ligand-dependent regulations were identified, which may modulate the response of macrophages to bacterial infections, but also the commensal microbiota through changes in immune cell signaling and metabolic pathways that may also alter functionality. These findings highlight the relevance of AhR for maintaining microbial homeostasis and, consequently, host health.
Highlights
The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds to endogenous metabolites and xenobiotic chemicals that feature an aromatic ring system, serving as an environmental sensor
AhR is released from the cytosolic complex and translocates to the nucleus, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT)
We and others have shown that AhR activation by exogenous ligands leads to anti-inflammatory effects in activated macrophages [26,27]
Summary
The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds to endogenous metabolites and xenobiotic chemicals that feature an aromatic ring system, serving as an environmental sensor. It has recently gained emerging interest due to its safeguarding barrier function in the intestines [1]. AhR is released from the cytosolic complex and translocates to the nucleus, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT). The AhR-ARNT complex is recruited to xenobiotic response elements (XRE), initiating target gene expression [6], e.g., CYP1A1, CYP1B1, IDO1, and TDO2, as well as the aryl hydrocarbon receptor repressor (AHRR), providing a negative feedback loop [7]. Benzo(a)pyrene (BaP) is a prototypic, widespread PAH mainly originating from incomplete combustion that may occur during tobacco smoking [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: International Journal of Environmental Research and Public Health
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
