Endothelial AHR activity prevents lung barrier disruption in viral infection

Abstract

Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function 1 . Endothelial dysfunction is known to exacerbate tissue damage 2 , 3 , yet it is unclear whether the lung endothelium promotes host resistance against viral pathogens. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is highly active in lung endothelial cells and protects against influenza-induced lung vascular leakage. Loss of AHR in endothelia exacerbates lung damage and promotes infiltration of red blood cells and leukocytes into alveolar air spaces, compromises barrier protection, and increases host susceptibility to secondary bacterial infections. AHR engages tissue-protective transcriptional networks in endothelia, including the vasoactive apelin/APJ peptide system 4 , to prevent a dysplastic and apoptotic response in airway epithelial cells. Finally, we show that protective AHR signalling in lung endothelial cells is dampened by the infection itself. Maintenance of protective AHR function requires a diet enriched in naturally occurring AHR ligands, which activate disease tolerance pathways in lung endothelia to prevent tissue damage. Our findings demonstrate the importance of endothelial function in lung barrier immunity. We identify a gut-lung axis which affects lung damage upon encounter with viral pathogens, linking dietary composition and intake to host fitness and inter-individual variations in disease.

Lung-Gut Microbiota and Tryptophan Metabolites Changes in Neonatal Acute Respiratory Distress Syndrome

“… 54 , 55 They can participate in respiratory system diseases by activating AhR, which is widely expressed and highly active in the lung barrier and immune system. 24 , 56 Previous studies have found that ICA exhibits anti-allergic and antimicrobial effects, while indole-3-acetic acid (IAA) may alleviate inflammation through IL-22, exerting protective effects in respiratory system diseases. 57–59 However, the role of ILA remains controversial, potentially exerting protective effects in conditions such as tumors and neurodegeneration, or being associated with chronic kidney disease, cisplatin-induced intestinal pathology, and colitis.…”

“… 19–23 According to recent studies, AhR is highly active in lung endothelial cells and is a crucial player in lung barrier immunity and the immune response in respiratory diseases. 24 Currently, there have been no reports on the microbiota composition and tryptophan metabolites in newborns with NARDS. Therefore, exploring the changes in microbial structure and tryptophan metabolites in NARDS is of significant importance.…”

Aryl hydrocarbon receptor restricts axon regeneration of DRG neurons in response to injury

“…In a Huntington’s disease model, Ahr deletion led to protection against neurotoxicity and oxidative stress 80 . Recent studies also reported the role of endothelial AhR signaling in integrating dietary cues to maintain tissue homeostasis 81 and exerting protective function in the gut-lung axis 82 . AhR is also important for timely termination of the regenerative response of intestinal epithelia by restricting chromatin accessibility of regeneration-associated Yap/Tead target genes in colonic stem cells 83 .…”

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

“…AT2 cells were isolated from naïve mice as previously described (26,36,37). Briefly, mouse lungs were perfused with chilled PBS and intratracheally instilled with 1mL of dispase II (15U/mL, Roche), tying off the trachea and cutting away the lobes from the mainstem bronchi.…”

“…Fluorescence assisted cell sorting was performed on the BD Influx cell sorter to isolate AT2 cells as described previously (36) and collected in 500μL DMEM + 40% FBS + 2% P/S. Sorted AT2 cells (2x10 5 /well) were plated in a 96-well plate in DMEM/F12 + 10% FBS and cultured at 37°C, 5% CO 2 for 3 days prior to harvest.…”