Circadian clock component REV-ERBá controls homeostatic regulation of pulmonary inflammation

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic Inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBa as essential to the mechanism coupling the pulmonary clock to Innate Immunity, Involving both myeloid and bronchial epithelial cells In temporal gating and determining amplitude of response to Inhaled endotoxin. Dual mutation of REV-ERBa and Its paralog REV-ERBß in bronchial epithelia further augmented inflammatory responses and chemoklne activation, but also Initiated a basal Inflammatory state, revealing a critical homeostatic role for REV-ERB proteins In the suppression of the endogenous prolnflammatory mechanism In unchallenged cells. However, REV-ERBa plays the dominant role, as deletion of REV-ERBß alone had no impact on Inflammatory responses. In turn, Inflammatory challenges cause striking changes In stability and degradation of REV-ERBa protein, driven bySUMOylationand ublquitlnatlon. We developed a novel selective oxazole-based Inverse agonist of REV-ERB, which protects REV-ERBa protein from degradation, and used this to reveal how prolnflammatory cytokines trigger rapid degradation of REV-ERBa In the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBa protein couple the core clock to Innate immunity.