Transcriptomic signatures reveal a shift towards an anti-inflammatory gene expression profile but also the induction of type I and type II interferon signaling networks through aryl hydrocarbon receptor activation in murine macrophages

• DOI: 10.3389/fimmu.2023.1156493
• Publication Date: 2023-05-23T04:34:01Z
• Authors: Johannes R. Schmidt; Janine Haupt; Sina Riemschneider; Christoph Kämpf; Dennis Löffler; Conny Blumert; Kristin Reiche; Ulrike Koehl; Stefan Kalkhof; Jörg Lehmann
• Keywords: Proinflammatory cytokine

Introduction The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates broad range of target genes involved in the xenobiotic response, cell cycle control and circadian rhythm. AhR constitutively expressed macrophages (Mϕ), acting as key regulator cytokine production. While proinflammatory cytokines, i.e., IL-1β, IL-6, IL-12, are suppressed through activation, anti-inflammatory IL-10 induced. However, underlying mechanisms those effects importance specific ligand structure not yet completely understood. Methods Therefore, we have compared global gene expression pattern activated murine bone marrow-derived (BMMs) subsequently to exposure with either benzo[ ]pyrene (BaP) or indole-3-carbinol (I3C), representing high-affinity vs. low-affinity ligands, respectively, by means mRNA sequencing. dependency observed was proved using BMMs from AhR-knockout ( Ahr -/- ) mice. Results discussion In total, more than 1,000 differentially (DEGs) could be mapped, covering plethora AhR-modulated on basal cellular processes, translation, but also immune functions, antigen presentation, production, phagocytosis. Among DEGs were already known regulated AhR, Irf1 , Ido2 Cd84 . identified described AhR-regulated Mϕ so far, Slpi Il12rb1 Il21r. All six likely contribute shifting phenotype anti-inflammatory. majority induced BaP affected I3C exposure, probably due higher affinity comparison I3C. Mapping response element (AHRE) sequence motifs revealed 200 possessing any AHRE, therefore being eligible for canonical regulation. Bioinformatic approaches modeled central role type I II interferons regulation genes. Additionally, RT-qPCR ELISA confirmed AhR-dependent expressional induction secretion IFN-γ suggesting an auto- paracrine activation pathway Mϕ.