The molecular circadian clock of eosinophils: a potential therapeutic target for asthma
Abstract
Asthma is a chronic inflammatory airway disease exhibiting time-of-day variability in symptoms and severity. Eosinophils, pivotal players and biomarkers in asthma, are regulated by the molecular circadian clock. This study aimed to investigate the impact of the molecular circadian clock on eosinophil effector function and its potential as a diagnostic biomarker and therapeutic target. We monitored clock proteins by flow cytometry in peripheral blood eosinophils from participants with mild asthma over a 24-h period. The observed decreased protein levels were confirmed in a cohort of patients with moderate asthma. To assess the interaction between inflammation and the molecular circadian clock, eosinophils were stimulated with patients' sera, inflammatory mediators, and clock-modulating ligands. The therapeutic potential of the inverse retinoic acid receptor-related-related orphan receptor (ROR) agonist SR1001 was evaluated in vitro and in a murine model of allergen-induced airway inflammation. Altered protein levels of circadian locomotor output cycles kaput (CLOCK), Brain and muscle Arnt-like protein-1 (BMAL1), REV-ERBs, and RORs in eosinophils from participants with asthma reflected the disease severity and allergy status of the patients. Mimicking an inflammatory environment in vitro resulted in similar changes. Blocking C-C chemokine receptor type 3 (CCR3)/ERK and epidermal growth factor receptor (EGFR) signaling with an inverse ROR agonist SR1001 reset the molecular…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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