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The circadian clock protein REVERBα inhibits pulmonary fibrosis development

Lookup NU author(s): Dr Lee Borthwick, Professor Andrew Fisher

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Copyright © 2020 the Author(s). Published by PNAS.Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.


Publication metadata

Author(s): Cunningham PS, Meijer P, Nazgiewicz A, Anderson SG, Borthwick LA, Bagnall J, Kitchen GB, Lodyga M, Begley N, Venkateswaran RV, Shah R, Mercer PF, Durrington HJ, Henderson NC, Piper-Hanley K, Fisher AJ, Chambers RC, Bechtold DA, Gibbs JE, Loudon AS, Rutter MK, Hinz B, Ray DW, Blaikley JF

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2020

Volume: 117

Issue: 2

Pages: 1139-1147

Print publication date: 14/01/2020

Online publication date: 26/12/2019

Acceptance date: 02/04/2019

Date deposited: 11/05/2020

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.1912109117

DOI: 10.1073/pnas.1912109117

PubMed id: 31879343


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