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

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 & 6 others Andrew S. MacDonald, Brian Bolognese, Patricia L. Podolin, Yolanda Sanchez, Andrew S.I. Loudon, David W. Ray

Research output: Contribution to journalArticle

  • 3 Citations

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-ERBß 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-ERBß 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.

LanguageEnglish
Pages2281-2296
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number6
Early online date13 Mar 2018
DOIs
StatePublished - 1 Jun 2018

Fingerprint

Circadian Clocks
Pneumonia
Innate Immunity
Epithelial Cells
Oxazoles
Sumoylation
Lung
Proteins
Ubiquitination
Chemokines
Endotoxins
Proteolysis
Epithelium
Cytokines
Mutation

Keywords

  • inflamation
  • pulmonology

Cite this

Pariollaud, M., Gibbs, J. E., Hopwood, T. W., Brown, S., Begley, N., Vonslow, R., ... Ray, D. W. (2018). Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. Journal of Clinical Investigation, 128(6), 2281-2296. DOI: 10.1172/JCI93910
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. ; Ray, David W./ Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 6. pp. 2281-2296
@article{894b1c6e7fc6404fae469a03c22a7cb7,
title = "Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation",
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-ERB{\ss} 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-ERB{\ss} 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 = "inflamation, pulmonology",
author = "Marie Pariollaud and Gibbs, {Julie E.} and Hopwood, {Thomas W.} and Sheila Brown and Nicola Begley and Ryan Vonslow and Toryn Poolman and Baoqiang Guo and Ben Saer and Jones, {D. Heulyn} and Tellam, {James P.} and Stefano Bresciani and Tomkinson, {Nicholas C.O.} and Justyna Wojno-Picon and Cooper, {Anthony W.J.} and Daniels, {Dion A.} and Trump, {Ryan P.} and Daniel Grant and William Zuercher and Willson, {Timothy M.} and MacDonald, {Andrew S.} and Brian Bolognese and Podolin, {Patricia L.} and Yolanda Sanchez and Loudon, {Andrew S.I.} and Ray, {David W.}",
year = "2018",
month = "6",
day = "1",
doi = "10.1172/JCI93910",
language = "English",
volume = "128",
pages = "2281--2296",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "6",

}

Pariollaud, M, Gibbs, JE, Hopwood, TW, Brown, S, Begley, N, Vonslow, R, Poolman, T, Guo, B, Saer, B, Jones, DH, Tellam, JP, Bresciani, S, Tomkinson, NCO, Wojno-Picon, J, Cooper, AWJ, Daniels, DA, Trump, RP, Grant, D, Zuercher, W, Willson, TM, MacDonald, AS, Bolognese, B, Podolin, PL, Sanchez, Y, Loudon, ASI & Ray, DW 2018, 'Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation' Journal of Clinical Investigation, vol. 128, no. 6, pp. 2281-2296. DOI: 10.1172/JCI93910

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.; Ray, David W.

In: Journal of Clinical Investigation, Vol. 128, No. 6, 01.06.2018, p. 2281-2296.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation

AU - Pariollaud,Marie

AU - Gibbs,Julie E.

AU - Hopwood,Thomas W.

AU - Brown,Sheila

AU - Begley,Nicola

AU - Vonslow,Ryan

AU - Poolman,Toryn

AU - Guo,Baoqiang

AU - Saer,Ben

AU - Jones,D. Heulyn

AU - Tellam,James P.

AU - Bresciani,Stefano

AU - Tomkinson,Nicholas C.O.

AU - Wojno-Picon,Justyna

AU - Cooper,Anthony W.J.

AU - Daniels,Dion A.

AU - Trump,Ryan P.

AU - Grant,Daniel

AU - Zuercher,William

AU - Willson,Timothy M.

AU - MacDonald,Andrew S.

AU - Bolognese,Brian

AU - Podolin,Patricia L.

AU - Sanchez,Yolanda

AU - Loudon,Andrew S.I.

AU - Ray,David W.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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-ERBß 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-ERBß 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.

AB - 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-ERBß 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-ERBß 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.

KW - inflamation

KW - pulmonology

UR - http://www.scopus.com/inward/record.url?scp=85048260311&partnerID=8YFLogxK

UR - https://www.jci.org/

U2 - 10.1172/JCI93910

DO - 10.1172/JCI93910

M3 - Article

VL - 128

SP - 2281

EP - 2296

JO - Journal of Clinical Investigation

T2 - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -

Pariollaud M, Gibbs JE, Hopwood TW, Brown S, Begley N, Vonslow R et al. Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. Journal of Clinical Investigation. 2018 Jun 1;128(6):2281-2296. Available from, DOI: 10.1172/JCI93910