Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption

Abstract

Circadian rhythms and sex differences are involved in the pathophysiology of asthma. Yet, there are no reports that simultaneously address the role of the circadian clock and sex-based differences in chronic house dust mite (HDM)-induced asthma. Here, we sought to determine if chronic HDM exposure during the resting phase (zeitgeber time: ZT0/6:00 a.m.) versus the active phase (ZT12/6:00 p.m.) differentially affects the circadian clock and alters asthma pathobiology in female and male mice. HDM exposure at ZT12 exaggerated infiltration of eosinophil subtypes and associated chemokines in females compared to males. Furthermore, HDM exposure augmented eosinophil chemokines, Th2 gene expression and cytokine release, and humoral immune response in females compared to males at ZT12. Concurrently, histopathological evaluation confirmed increased airway inflammation at ZT12 in both females and males. Overall, we showed a time-of-day response and sex-based differences in HDM-induced exaggerated asthmatic phenotypes (inflammation/remodeling) and circadian clock disruption in females compared to males.