The aryl hydrocarbon receptor regulates lipid mediator production in alveolar macrophages

Frontiers in Immunology

Immunology

Fiona Henkel¹  Ann-Marie Maier¹  Benjamin Schnautz¹  Caspar Ohnmacht¹  Anela Arifovic¹  Karsten Huth¹  Francesca Alessandrini¹  Julia Esser-von-Bieren²  Carsten B. Schmidt-Weber³  Katrin Sameith⁴  Anja Koegler⁴  Mark Haid⁵  Fabien Riols⁵ 

[1] Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Research Center for Environmental Health, Neuherberg, Germany;Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Research Center for Environmental Health, Neuherberg, Germany;Department of Immunobiology, University of Lausanne, Epalinges, Switzerland;Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, Research Center for Environmental Health, Neuherberg, Germany;Member of the German Center of Lung Research (DZL), Partner Site Munich, Munich, Germany;DRESDEN-concept Genome Center, Technology Platform at the Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany;Metabolomics and Proteomics Core, Helmholtz Center Munich, Research Center for Environmental Health, Neuherberg, Germany;

关键词: macrophage;    aryl hydrocarbon receptor;    eicosanoids;    leukotriene;    prostaglandin;   

DOI  :  10.3389/fimmu.2023.1157373

 received in 2023-02-02, accepted in 2023-03-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.

【 授权许可】

Unknown   
Copyright © 2023 Maier, Huth, Alessandrini, Henkel, Schnautz, Arifovic, Riols, Haid, Koegler, Sameith, Schmidt-Weber, Esser-von-Bieren and Ohnmacht