Gut Signals Influence Lung Responses to Infection
Diet-derived molecules spur a biological mechanism in the lung barriers of mice that prevents viral lung injury.
Andreas Wack’s research at the Francis Crick Institute focuses on understanding what influences the severity of viral infections in the lungs. An immunologist by training, Wack studied immune and lung epithelial cells for years before realizing that the lung endothelial cells, which are part of the lung barrier, could be key to an organism’s response to a viral infection.
Evidence suggested that the aryl hydrocarbon receptor (AHR) is essential for airway epithelia and gut barrier immunity.1,2 So, Wack led a team of scientists to investigate the function of AHR in the lung endothelium. In the journal Nature, he and his collaborators described how AHR signaling prevents endothelium damage after an infection and pinpointed the contribution of dietary AHR ligands to this end.3
“Looking at the endothelium in terms of barrier function is not entirely new,” said Wolfgang Kuebler, a lung and cardiovascular physiologist at the Charité University Berlin who was not involved in the research. “But looking at how the endothelium regulates the epithelium and thereby improves barrier function, that is what matters because both cells compose the barrier and work together.”
Wack’s team used mice that either lacked AHR or did not metabolize its ligands, leading them to build up. After a viral infection, mice lacking the receptor showed signs of lung injury that were prevented in animals with excess AHR ligands.
By assessing gene expression changes in endothelial cells, the team found that AHR-deficient mice showed disruption of the apelin signaling pathway, which is involved in vessel function regulation. Treating mice with apelin reduced lung damage after infection in wild type but not in AHR-deficient mice, suggesting a role for AHR-apelin signaling in lung protection.
AHR ligands come from the diet (mainly from cruciferous vegetables) or from the metabolism of gut bacteria, so the team next tested whether adding an AHR ligand to the mouse food would affect AHR activity and disease progression. The enriched diet led to fewer signs of lung damage, which according to Wack, provides an example of how gut-derived molecules can affect barrier integrity in other parts of the body.
“A lesson for all immunologists is that you want to embed your lung immune response research into a bigger context,” said Wack. “The lung is clearly communicating with other barrier sites and organs, and we need to think about this.”