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

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without an effective cure. Herein, we explore the role of 3,5,3′-triiodothyronine (T(3)) administration on lung alveolar regeneration and fibrosis at the single-cell level. T(3) supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury; there were much more M2 macrophages than M1 macrophages in the lungs of bleomycin-treated mice; and M1 macrophages increased slightly, whereas M2 macrophages were significantly reduced after T(3) treatment. T(3) enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8(+) transitional alveolar type II epithelial cells into alveolar type I epithelial cells and inhibiting fibroblast activation and extracellular matrix production potentially by regulation of Nr2f2. In addition, T(3) 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.