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J Clin Invest. 2018 Jun 1;128(6):2281-2296. doi: 10.1172/JCI93910. Epub 2018 Apr 30.

Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation.

Author information

1
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
2
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United Kingdom.
3
GlaxoSmithKline R&D, Stevenage, United Kingdom.
4
Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
5
Novartis AG, East Hannover, New Jersey, USA.
6
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
7
Stress and Repair Discovery Performance Unit, Respiratory Therapy Area, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

Abstract

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.

KEYWORDS:

Inflammation; Innate immunity; Mouse models; Neutrophils; Pulmonology

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