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Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1139-1147. doi: 10.1073/pnas.1912109117. Epub 2019 Dec 26.

The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Author information

1
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
2
The George Alleyne Chronic Disease Research Centre, The University of the West Indies, Bridgetown. Barbados BB11000.
3
Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
4
Manchester University National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom.
5
Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada.
6
Centre for Inflammation and Tissue Repair, Faculty of Medical Sciences, University College London, London WC1E 6JJ, United Kingdom.
7
Centre for Inflammation Research, University of Edinburgh, EH16 4TJ Edinburgh, United Kingdom.
8
Institute of Transplantation, Freeman Hospital, The Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne NE7 7DN, United Kingdom.
9
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
10
National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
11
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, United Kingdom.
12
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom; john.blaikley@manchester.ac.uk.

Abstract

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.

KEYWORDS:

Reverb alpha; circadian; integrin; pulmonary fibrosis; sleep

PMID:
31879343
DOI:
10.1073/pnas.1912109117
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Conflict of interest statement

The authors declare no competing interest.

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