TRβ 激活通过 KLF2 和 CEBPA 赋予 AT2 向 AT1 细胞分化和抗纤维化作用，从而促进肺修复。

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA.

机构信息

Pingyuan Laboratory, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang, China.

State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

Nat Commun. 2024 Oct 7;15(1):8672. doi: 10.1038/s41467-024-52827-z.

DOI:10.1038/s41467-024-52827-z

PMID:39375377

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11458772/

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.

摘要

异常修复是肺纤维化发病机制的基础，而将纤维化转化为正常再生的有效策略却很少。在这里，我们发现甲状腺激素在多种肺损伤模型中减少，但对肺再生是必需的。此外，甲状腺激素受体α（TRα）促进细胞增殖，而 TRβ 在肺再生中促进细胞成熟。我们使用一种特异性的 TRβ 激动剂，索比替罗，证明了甲状腺激素的抗纤维化作用主要依赖于 TRβ 在小鼠中的作用。在细胞水平上，TRβ 的激活增强了肺泡型 2（AT2）细胞向 AT1 细胞的分化，并抑制了 AT2 细胞的过度增生。在分子水平上，TRβ 的激活直接调控 KLF2 和 CEBPA 的表达，这两者进一步协同地驱动 AT1 细胞的分化程序，并有利于再生和抗纤维化。我们的研究结果阐明了 TRβ-KLF2/CEBPA 轴对 AT2 细胞命运的调节功能，并为促进肺再生和抗纤维化提供了一种潜在的治疗策略。