Exposure to a common fungal molecule can reprogram immune cells in the lungs, causing them to overreact to infection-like signals and worsen lung damage, according to new research.
The study, published today in eLife as the Version of Record after previously appearing as a Reviewed Preprint, is described by the editors as important for advancing our understanding of maladaptive trained immunity. They add that the strength of evidence is convincing, and that the manuscript is strongly endorsed by the expert reviewers. The work will be of high interest to both researchers in the trained immunity field and clinician scientists.
Trained immunity refers to a type of long-term ‘memory’ in the innate immune system – the body’s first line of defence against infections. Unlike the adaptive immune system, which learns to recognise specific viruses or bacteria, trained immunity enhances general responsiveness of innate immune cells to a broad range of triggers. This is driven by lasting changes in the cells’ gene expression and metabolism. While trained immunity is being explored as a way to boost protection through vaccines or therapies, recent research is beginning to show that it can also have negative effects in certain contexts.
Alveolar macrophages are immune cells that reside permanently in the air sacs (alveoli) of the lungs. They are essential for maintaining lung health by clearing inhaled pathogens, particles and cellular debris. The fungal molecule β-glucan is a known trigger of trained immunity in the bone marrow, where it reprograms stem cells to produce more reactive immune cells.
“To date, most trained immunity research has focused on circulating immune cells that arise from the bone marrow,” says lead author Renaud Prével, a postdoctoral research fellow at the Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, McGill University, Canada. “We wanted to explore whether β-glucan could induce trained immunity in alveolar macrophages, and whether that might be helpful or harmful.”
To test this, Prével and colleagues administered a single dose of purified β-glucan to mice. After a week, they exposed the mice to molecules that mimic bacterial (lipopolysaccharide) or viral (poly(I:C)) infection. These mimics are known to trigger lung inflammation and injury.
Using high-resolution microCT scans and fluid analysis, they found that mice pre-treated with β-glucan developed significantly more severe lung injury compared to untreated controls. They observed more poorly-aerated regions in the lungs, thicker alveolar walls, and visible signs of inflammation such as heightened immune cell infiltration.
Notably, the number of alveolar macrophages present in the lungs of treated mice remained unchanged. Instead, existing alveolar macrophages had been reprogrammed to behave differently. They produced more inflammatory molecules and recruited more neutrophils – a type of immune cell known to amplify inflammation.
To confirm these cells were responsible for the increased inflammation, the researchers then selectively depleted alveolar macrophages in mice and exposed them to the bacterial and viral mimics. This prevented the excess lung inflammation. In addition, they transferred trained alveolar macrophages into mice lacking their own, and observed the same heightened inflammatory response, showing that the reprogramming of alveolar macrophages by β-glucan was long-lasting and intrinsic to the cells.
Next, the team looked to establish how this reprogramming occurs. Using gene sequencing and metabolic profiling, they found that trained alveolar macrophages had an altered expression of immune genes and increased energy metabolism – classic hallmarks of trained immunity.
Unexpectedly, the reprogramming process did not depend on Dectin-1, the usual receptor for β-glucan, nor did it require type I interferons, which are often involved in immune memory. Instead, it required interferon-gamma, a signalling molecule typically produced during infection, and the presence of neutrophils. Blocking the presence of either molecule prior to β-glucan exposure prevented the training of alveolar macrophages from occurring.
“Our study shows that immune memory in the lungs is more dynamic than previously thought,” concludes senior author and Principal Investigator Maziar Divangahi, Professor in the Department of Medicine and Associate Director of the Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, McGill University. “Alveolar macrophages can be trained by systemic signals, and that training can have detrimental consequences under certain conditions. This could help explain why some individuals develop more severe lung inflammation, especially in settings like sepsis.”
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