Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Pariollaud, Marie, Gibbs, Julie E., Hopwood, Thomas W., Brown, Sheila, Begley, Nicola, Vonslow, Ryan, Poolman, Toryn, Guo, Baoqiang, Saer, Ben, Jones, D. Heulyn, Tellam, James P., Bresciani, Stefano, Tomkinson, Nicholas C.O., Wojno-Picon, Justyna, Cooper, Anthony W.J., Daniels, Dion A., Trump, Ryan P., Grant, Daniel, Zuercher, William, Willson, Timothy M., MacDonald, Andrew S., Bolognese, Brian, Podolin, Patricia L., Sanchez, Yolanda, Loudon, Andrew S.I. and Ray, David W. 2018. Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. Journal of Clinical Investigation 128 (6) , pp. 2281-2296. 10.1172/JCI93910

[thumbnail of 93910.3-20180522131823-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf] PDF - Published Version
Available under License Creative Commons Attribution.

Download (8MB)

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of First Compliant Deposit: 14 May 2020
Date of Acceptance: 8 March 2018
Last Modified: 04 May 2023 19:23
URI: https://orca.cardiff.ac.uk/id/eprint/131629

Citation Data

Cited 95 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics