The Role and Mechanism of Pulmonary ILC2 in Diesel Exhaust-Exacerbated Airway Allergies
Diesel exhaust (DE), a principal component of traffic-related air pollution, constitutes a significant concern for both public and occupational health. Allergic airway inflammation constitutes a highly prevalent respiratory disorder that is elicited by environmental exposure to aeroallergens, including, but not limited to, house dust mite (HDM). Epidemiological and observational data from real-world environments indicate that DE frequently co-occurs with airborne allergens, resulting in concurrent exposure in human populations. Previous investigations in individuals with allergic disease have demonstrated that exposure to DE exacerbates allergen-induced inflammatory responses in the airways. More recently, group 2 innate lymphoid cell (ILC2) have been identified as pivotal effector populations in mediating these DE-enhanced allergic airway reactions. ILC2 are activated in response to a broad spectrum of epithelial-derived alarmins and, upon stimulation, rapidly secrete type 2 cytokines that potentiate and propagate downstream inflammatory cascades. Moreover, the recruitment, maintenance, and functional activation of ILC2 are closely intertwined with lipid metabolic pathways, although the underlying molecular mechanisms remain incompletely elucidated. In this study, we investigated the mechanisms by which ILC2 is primed and regulated in the context of concomitant exposure to DE and HDM. We observed that co-exposure exacerbated pulmonary injury, characterized by enhanced airway mucus hypersecretion and pronounced structural remodeling of the airway architecture. The co-exposure group additionally exhibited increased accumulation of eosinophils and ILC2, accompanied by elevated pulmonary levels of type 2 cytokines. Moreover, co-exposure potentiated lipid droplet accumulation and altered lipid class distribution within the pulmonary microenvironment. Notably, pulmonary ILC2 from co-exposed mice exhibited a pronounced enrichment of cholesterol metabolism-related pathways. Collectively, these findings demonstrate that concurrent exposure to DE and HDM exacerbates allergic airway responses and further suggest that alterations in pulmonary lipid homeostasis may drive cholesterol metabolic reprogramming, thereby facilitating ILC2 activation. Our findings identify cholesterol metabolism as a novel mechanistic axis for elucidating how DE exacerbates allergic responses and suggest potential therapeutic targets for the treatment of respiratory diseases associated with environmental exposures.