Proteomic Characterization of the Cellular Effects of AhR Activation by Microbial Tryptophan Catabolites in Endotoxin-Activated Human Macrophages

Katharina Walter, Henning Grosskopf, Isabel Karkossa, Martin von Bergen and Kristin Schubert
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Katharina Walter: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany
Henning Grosskopf: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany
Isabel Karkossa: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany
Martin von Bergen: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany
Kristin Schubert: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany

IJERPH, 2021, vol. 18, issue 19, 1-18

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.

Keywords: AhR; macrophages; proteome; BaP; indoles; indole-3-acetic acid; indole-3-aldehyde; LPS (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2021
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