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Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation
- Source :
- Pariollaud, M, Gibbs, J, Hopwood, T, Brown, S, Begley, N, Vonslow, R, Poolman, T, Guo, B, Saer, B, Jones, D H, Tellam, J P, Bresciani, S, Tomkinson, N C, Wojno-Picon, J, Cooper, A W, Daniels, D A, Trump, R P, Grant, D, Zuercher, W, Willson, T M, MacDonald, A S, Bolognese, B, Podolin, P L, Sanchez, Y, Loudon, A S & Ray, D W 2018, ' Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation ', The Journal of clinical investigation, vol. 128, no. 6, pp. 2281-2296 . https://doi.org/10.1172/JCI93910, The Journal of Clinical Investigation
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Chemokine
Pulmonology
Neutrophils
viruses
Circadian clock
SUMO protein
Mice, Transgenic
Inflammation
Endogeny
Mouse models
Proinflammatory cytokine
Mice
03 medical and health sciences
Circadian Clocks
medicine
Animals
Homeostasis
Circadian rhythm
Innate immunity
Innate immune system
biology
Sumoylation
Pneumonia
General Medicine
Immunity, Innate
Circadian Rhythm
3. Good health
Cell biology
030104 developmental biology
Nuclear Receptor Subfamily 1, Group D, Member 1
Proteolysis
biology.protein
medicine.symptom
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Pariollaud, M, Gibbs, J, Hopwood, T, Brown, S, Begley, N, Vonslow, R, Poolman, T, Guo, B, Saer, B, Jones, D H, Tellam, J P, Bresciani, S, Tomkinson, N C, Wojno-Picon, J, Cooper, A W, Daniels, D A, Trump, R P, Grant, D, Zuercher, W, Willson, T M, MacDonald, A S, Bolognese, B, Podolin, P L, Sanchez, Y, Loudon, A S & Ray, D W 2018, ' Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation ', The Journal of clinical investigation, vol. 128, no. 6, pp. 2281-2296 . https://doi.org/10.1172/JCI93910, The Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....4b850d90e252cb0cef62edd168f157db