Endothelial AHR Signaling: A Key Regulator of Immune Defense

The endothelium is a site of increased AHR activity in the lung.Credit：https://doi.org/10.1038/s41586-023-06287-y

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that has long been recognized for its role in mediating the toxicity of environmental contaminants. However, recent studies have revealed that AHR may also play a critical role in maintaining normal physiological functions, especially in the context of immune defense. Major et al. investigated the role of the AHR in the lung endothelium in protecting against influenza virus infection-induced lung damage and identified a high level of AHR expression and activity in lung endothelial cells compared to other cell types, indicating a potential role for AHR in the lung endothelium. Mice deficient in the AHR downstream enzymes Cyp1a1, Cyp1b1, and Cyp1a2 (Cyp1-/-) displayed increased AHR signaling and reduced lung damage following influenza virus infection, indicating a protective role of AHR. This is further supported by endothelial-specific deletion of AHR, which exacerbates lung damage upon infection.

The authors then performed transcriptomic analysis to uncover the mechanisms underlying AHR's protective role in the lung endothelium. They identified dysregulated pathways in AHR-deficient endothelial cells covering stress response, metabolism, and cell death, and in epithelial cells isolated from AHR-deficient mice covering proliferation, cell signaling, and apoptosis. Notably, the apelin signaling pathway was disrupted in AHR-deficient endothelial cells, and apelin treatment reduced lung damage in wild type mice but not AHR-deficient mice.

The authors further investigated the regulation of AHR signaling in the lung endothelium, finding that AHR signaling was dampened in wild type mice upon influenza virus infection, which can be restored by dietary supplementation with the AHR ligand indole-3-carbinol (I3C). Dietary I3C confers protection against influenza-induced lung damage, dependent on AHR signaling in the endothelium and the apelin pathway.

In summary, this study revealed that AHR signaling in the lung endothelium might serve as a critical host defense mechanism against influenza virus infection-induced lung damage. AHR promoted endothelial barrier function and prevented epithelial apoptosis and dysplasia. The apelin signaling pathway has been identified as a key mediator of AHR's protective effects. Furthermore, the study highlighted the gut-lung axis, where dietary AHR ligands regulate AHR signaling in the lung endothelium, which may affect the susceptibility to influenza virus infection and severity of lung disease. This work underscores the importance of endothelial function in coordinating the tissue response to respiratory viral infections.

Another similar study conducted by Wiggins et al. investigated the role of the aryl hydrocarbon receptor (AHR) in endothelial cells, focusing on its impact on intestinal homeostasis. First, they established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic endothelial cells. Single-cell RNA sequencing revealed 11 endothelial clusters, clearly demarcated across two superclusters: lymphatic endothelial cells (LECs) and blood endothelial cells (BECs). The study further showed that the AHR acted as a critical node for endothelial cell sensing of dietary metabolites in adult mice and human primary endothelial cells. AHR-mediated responses identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. The study then generated an inducible endothelial cell-specific Ahr-deficient mouse model, and found that endothelial AHR deficiency in adult mice resulted in dysregulated inflammatory responses and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric bacterial infection.

In human endothelial cells, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, these data provide a comprehensive dissection of the effect of environmental sensing across the spectrum of enteric endothelia, revealing that endothelial AHR signalling may integrate dietary cues to maintain tissue homeostasis by promoting endothelial cell quiescence and vascular normalcy.

Taken together, these studies find that AHR is highly active in endothelial cells of the respective organ systems and underscores the critical role of AHR signaling in endothelial cells in maintaining barrier function and regulating inflammation. In the lung, AHR signaling may protect against influenza-induced lung damage, while in the intestine, AHR signaling may inhibit bacterial infection. Notably, the impact of dietary factors on AHR signaling illustrated in these two studies also highlights the importance of lifestyle factors in modulating AHR function and immune system.

1. Major J, Crotta S, Finsterbusch K, Chakravarty P, Shah K, Frederico B, D'Antuono R, Green M, Meader L, Suarez-Bonnet A, Priestnall S, Stockinger B, Wack A. Endothelial AHR activity prevents lung barrier disruption in viral infection. Nature. 2023 Sep;621(7980):813-820.

2. Wiggins BG, Wang YF, Burke A, Grunberg N, Vlachaki Walker JM, Dore M, Chahrour C, Pennycook BR, Sanchez-Garrido J, Vernia S, Barr AR, Frankel G, Birdsey GM, Randi AM, Schiering C. Endothelial sensing of AHR ligands regulates intestinal homeostasis. Nature. 2023 Sep;621(7980):821-829.