Introduction
Asthma affects more than 300 million people worldwide and is often worsened by common triggers such as allergens and respiratory viruses. The airway epithelium, the layer of cells lining the lungs, is the first tissue to encounter these exposures and helps coordinate both inflammatory and antiviral immune responses. In asthma, these responses are often unbalanced, with excessive inflammation but weaker antiviral defense. Increasing evidence suggests that changes in cellular energy metabolism, particularly the way cells produce, store and use fats (lipid or fat metabolism) and the function of mitochondria, the cell’s main energy-producing structures, may contribute to this dysfunction. We therefore investigate whether altered fat metabolism is a characteristic of asthmatic airway epithelial cells and whether it is further modified by environmental triggers or allergen immunotherapy.
Methods
We combine several large-scale molecular datasets to study metabolic changes in asthma. Proteomic analyses, which measure many proteins at once, compare primary human bronchial epithelial cells from individuals with asthma and healthy controls. These cells are studied both in an immature state and after they have been grown into a more airway-like cell layer, as well as after exposure to rhinovirus A16, a common cold virus that can trigger asthma attacks. Metabolomic and lipidomic analyses measure small molecules and fats in bronchoalveolar lavage fluid, a fluid collected from the lower airways, to assess the lung environment in asthma before and after experimental rhinovirus infection. We also reanalyze single-cell RNA-sequencing data from a human house dust mite challenge study. This method measures gene activity in individual cells and allows us to determine whether different cell types respond differently. Finally, we analyze data from a placebo-controlled house dust mite allergen immunotherapy study in allergic asthma to explore whether disease-associated metabolic changes may be reversible.
Results
Preliminary analyses identify asthma-associated changes in epithelial metabolism. Proteomic profiling revealed differences between asthma-derived and healthy airway epithelial cells that depended on how mature the cells were. Several proteins involved in lipid metabolism, including ALOX15 and the fatty acid oxidation regulators CPT1A and CPT2, differed between the groups. Fatty acid oxidation is the process by which cells break down fats to generate energy. Metabolomic and lipidomic analyses of airway fluid also identified distinct metabolic profiles in asthma and additional changes after rhinovirus infection. Reanalysis of single-cell data from house dust mite challenge showed that allergen exposure alters genes involved in fat metabolism differently across epithelial cell types, including ciliated cells, which help clear material from the airways, and mucus-producing cells. Preliminary findings from the allergen immunotherapy study additionally indicate that house dust mite immunotherapy improves epithelial antiviral responsiveness, including increased production of interferon beta, an important antiviral signaling molecule, after stimulation that mimics viral infection. Exploratory analyses also suggest broader metabolic changes after immunotherapy than after placebo treatment.
Discussion
Together, these findings suggest that asthma is associated with changes in how airway epithelial cells process and use energy, particularly fats, and that these changes are influenced by allergens, respiratory viruses and treatment. The results point towards altered lipid handling and mitochondrial fatty acid oxidation as possible mechanisms linking cellular metabolism to excessive airway inflammation and weaker antiviral defense. Ongoing experiments will test whether directly modifying these pathways changes epithelial immune responses. Understanding these mechanisms may reveal new ways to restore healthier airway responses and could help explain how allergen immunotherapy produces long-term disease modification beyond symptom control.