Single-Cell RNA-seq Provides New Insights into Therapeutic Roles of Thyroid Hormone in the Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without effective cure. Herein, we explore the role of 3,5,3’-triiodothyronine (T3) administration on lung alveolar regeneration and fibrosis at the single-cell level. T3 supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury, M2 macrophages were much than M1 macrophages in bleomycin-treated lungs, and M1 macrophages increased slightly, while M2 macrophages significantly reduced after T3 treatment. T3 enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8+ transitional alveolar type II epithelial cells (AT2) into alveolar type I epithelial cells (AT1) and inhibiting fibroblast activation and extracellular matrix (ECM) production potentially by regulation of Nr2f2. In addition, T3 regulated the crosstalk of macrophages with fibroblasts and the Pros1-Axl signaling axis significantly facilitated the attenuation of fibrosis. The findings demonstrate that administration of a thyroid hormone promotes alveolar regeneration and resolves fibrosis mainly by regulation of the cellular state and cell–cell communication of alveolar epithelial cells, macrophages, and fibroblasts in mouse lungs in comprehensive ways.