AHR is a protein found at barrier sites like the gut and lungs, and its effect on immune cells is well understood, this study demonstrated that AHR is also highly active in endothelial cells lining blood vessels in the lung.
The lung barrier between the body and outside air is made up of two layers, endothelial cells and epithelial cells, it needs to allow oxygen to enter but the barrier also needs to be kept strong against pollution, viruses, and bacteria.
To show how AHR impacts lung barriers a series of experiments were conducted in mice. When the animals were infected with the flu blood was found within the airspaces in the lungs as the barrier was damaged and it leaked across. However, when AHR was overactivated less blood was found in the lung spaces, demonstrating how AHR was able to help the barrier from becoming damaged/leaky.
Additionally, the animals with enhanced AHR activity were found not to lose as much weight when infected with the flu, and they were better able to fight off a bacterial infection on top of the original flu virus compared to those without enhanced AHR activity.
When the aryl hydrocarbon receptor was prevented from being expressed in lung endothelial cells of infected animals, the researchers report that they found more blood and immune cells in the air spaces of the lungs, demonstrating greater damage to the lung barrier.
Flu infection was shown to cause a decrease in protective lung AHR activity, but only in animals that were fed AHR ligands before illness, which suggests there may be a link between food consumption to AHR activity and the outcome of viral infection. Infected mice did not consume as much food when they were ill, so the intake of AHR ligands was reduced and the AHR system was less active resulting in more lung barrier damage.
Despite infection-driven reduction of AHR activity, it was beneficial for the animals to be on an AHR ligand-rich diet as they had better barrier integrity and less lung damage during infection than control animals indicating that AHR has a protective effect on the lung barrier which is impacted by infection but can be improved with the right diet.
“Until recently, we’ve mainly looked at barrier protection through the lens of immune cells. Now we’ve shown that AHR is important for maintaining a strong barrier in the lungs through the endothelial cell layer, which is disrupted during infection,” said Andreas Wack, Group Leader of the Immunoregulation Laboratory at the Crick. “People may be less likely to maintain a good diet when they’re ill, so aren’t taking in the molecules from vegetables which make this system work. It’s a good idea to eat lots of cruciferous vegetables anyway, but this shows it’s even more important to continue eating them when you’re ill!”
“What we’ve identified is a gut-lung axis — linking diet to protection against lung infection via endothelial cells,” said Jack Major, first author and former Ph.D. student in the Wack lab and now visiting scientist at Crick.”We looked at flu in this research, but other research has shown that COVID-19 may also reduce AHR activity in the lung. It will be interesting to investigate the impact of other respiratory viruses on AHR, and also whether different molecules in our diet use other pathways than AHR to affect lung function via endothelial cells.”
The researchers believe that AHR may also be important in endothelial cells in other barrier organs. Their work is in line with other research (published in Nature) showing that dietary factors activate AHR in gut endothelial cells which helps to prevent excessive cell reproduction and inflammation, that work shows gut endothelial AHR is important against gut infections providing another link between diet and the state of the gut endothelium which is an important contributor to gut health.
