TRβ Activation Confers AT2-to-AT1 Cell Differentiation and Anti-Fibrosis During Lung Repair via KLF2 and CEBPA

Authors

Xin Pan
Lan Wang
Juntang Yang
Yingge Li
Min Xu
Chenxi Liang
Lulu Liu
Zhongzheng Li
Cong Xia
Jiaojiao Pang
Mengyuan Wang
Meng Li
Saiya Guo
Peishuo Yan
Chen Ding
Ivan O Rosas
Guoying Yu

Publication Date

10-7-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-52827-z

PMID

39375377

PMCID

PMC11458772

PubMedCentral® Posted Date

10-7-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Kruppel-Like Transcription Factors, Cell Differentiation, Mice, Lung, Pulmonary Fibrosis, Mice, Inbred C57BL, Regeneration, Male, Alveolar Epithelial Cells, Cell Proliferation, Humans, Lung Injury, Disease Models, Animal, CCAAT-Enhancer-Binding Proteins, Hormone receptors, Mechanisms of disease, Target validation, Transcriptional regulatory elements

Abstract

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

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