Circadian clock component REV-ERB[alpha] 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-ERB[alpha] 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- ERB[alpha] and its paralog REV-ERB[beta] in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERB[alpha] plays the dominant role, as deletion of REV-ERB[beta] alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERB[alpha] protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERB[alpha] protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV- ERB[alpha] in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERB[alpha] protein couple the core clock to innate immunity.