There is a strong variation in pulmonary inflammation depending on the time of day. Airway epithelial cells have been shown to mediate rhythmic inflammatory responses, and loss of the central clock component BMAL1 in airway epithelium augments inflammation. It is not clear how BMAL1 regulates lung inflammation; however, REV-ERB transcription factors, have been proposed to regulate immune function downstream of BMAL1. In this episode, David Ray, Marie Pariollaud and colleagues provide evidence that REV-ERBα couples the pulmonary clock to innate immunity. Inflammatory stimuli were shown to promote REV-ERBα degradation, and complete lack of REV-ERBα further enhanced inflammation in the lungs in following inflammatory challenge. Together, these results identify REV-ERBα as a regulator of rhythmic inflammatory responses in the lung and provide rationale for further exploration of REV-ERBα as a target for inflammatory disease.
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-ERBα 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-ERBα and its paralog REV-ERBβ 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-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.
Marie Pariollaud, Julie E. Gibbs, Thomas W. Hopwood, Sheila Brown, Nicola Begley, Ryan Vonslow, Toryn Poolman, Baoqiang Guo, Ben Saer, D. Heulyn Jones, James P. Tellam, Stefano Bresciani, Nicholas C.O. Tomkinson, Justyna Wojno-Picon, Anthony W.J. Cooper, Dion A. Daniels, Ryan P. Trump, Daniel Grant, William Zuercher, Timothy M. Willson, Andrew S. MacDonald, Brian Bolognese, Patricia L. Podolin, Yolanda Sanchez, Andrew S.I. Loudon, David W. Ray