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Updated: Jan 1, 2026
Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures
Published on: November 11, 2016
The circadian clock protein REVERBα inhibits pulmonary fibrosis development
Peter S Cunningham1, Peter Meijer1, Alicja Nazgiewicz1
1Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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.
Insights
Circadian clock disruption in lung mesenchymal cells drives pulmonary fibrosis. Targeting the REVERBα protein offers a potential therapeutic strategy for idiopathic pulmonary fibrosis (IPF).
Area of Science:
- Pulmonary medicine
- Cell biology
- Chronobiology
Background:
- Circadian rhythms regulate pulmonary inflammation, but their role in fibrosis is unclear.
- Mesenchymal cells are key in pulmonary fibrosis pathogenesis.
- Core clock protein REVERBα's function in lung fibrosis is unknown.
Purpose of the Study:
- Investigate the role of circadian mechanisms in pulmonary fibrosis.
- Determine the impact of REVERBα in lung mesenchymal cells on fibrosis development.
- Explore REVERBα as a therapeutic target for idiopathic pulmonary fibrosis (IPF).
Main Methods:
- Utilized mouse models of bleomycin-induced pulmonary fibrosis.
- Genetically manipulated core clock protein REVERBα in specific lung cell types.
- Assessed fibrosis development, myofibroblast activation, and collagen secretion.
- Analyzed human cohorts (UK Biobank and IPF patient samples) for circadian markers and REVERBα expression.
Main Results:
- Disrupted REVERBα in lung mesenchymal cells exacerbated bleomycin-induced fibrosis.
- REVERBα regulates transcription factor TBPL1, impacting integrinβ1 focal-adhesion and myofibroblast activation.
- Circadian strain markers are risk factors for pulmonary fibrosis in humans.
- Increased REVERBα expression observed in human IPF lung tissue.
- Targeting REVERBα inhibited myofibroblast activation and collagen secretion in IPF models.
Conclusions:
- Circadian clock dysregulation in lung mesenchymal cells contributes to pulmonary fibrosis.
- REVERBα is a critical regulator of fibrosis development.
- REVERBα represents a promising therapeutic target for treating IPF.
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