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 mild asthmatics over a 24-hour 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 ROR agonist SR1001 was evaluated in vitro and in a murine model of allergen-induced airway inflammation. Altered protein levels of CLOCK, BMAL1, REV-ERBs, and RORs in eosinophils from asthmatics reflected the disease severity and allergy status of the patients. Mimicking an inflammatory environment in vitro resulted in similar changes. Blocking CCR3/ERK and EGFR signaling with an inverse ROR agonist SR1001 reset the molecular circadian clock in eosinophils and exhibited anti inflammatory effects by inhibiting eosinophil migration in vitro. Additionally, we confirmed the therapeutic potential of the clock-modulating SR1001, bronchoprotective effects in two in vivo models. This study suggests that clock proteins could serve as therapeutic targets in asthma. Pharmacological inhibition of ROR signaling demonstrated significant anti-inflammatory and bronchoprotective properties, indicating its potential as a novel treatment strategy for asthma and other eosinophilic diseases.