REV-ERBα deficiency exacerbates IL-33-mediated airway inflammation and airway hyperresponsiveness in mice.

Asthma involves type 2 airway inflammation driven by epithelial-derived interleukin-33 (IL-33), a key mediator of allergic responses. REV-ERBα, a circadian transcriptional repressor, modulates pulmonary inflammation, but its role in IL-33-induced airway pathology remains unclear. Here we investigated IL-33-mediated pulmonary inflammation in wild-type and global Rev-erbα knockout mice exposed intranasally to recombinant IL-33. Loss of REV-ERBα markedly increased recruitment of eosinophils, neutrophils, innate lymphoid cells, and Th2 lymphocytes, exacerbated airway hyperresponsiveness, and elevated chemokines linked to type 2 inflammation. REV-ERBα deficiency also altered circadian clock protein expression, enhanced IL-33/ST2 signaling, and reduced epithelial barrier-associated proteins. These findings indicate that REV-ERBα restrains IL-33-driven airway inflammation and hyperresponsiveness, suggesting circadian mechanisms influence asthma pathogenesis and highlighting REV-ERBα as a potential therapeutic target.