IRE1 alpha Drives Lung Epithelial Progenitor Dysfunction to Establish a Niche for Pulmonary Fibrosis

After lung injury, damage-associated transient progenitors (DATPs) emerge, representing a transitional state between injured epithelial cells and newly regenerated alveoli. DATPs express profibrotic genes, suggesting that they might promote idiopathic pulmonary fibrosis (IPF). However, the molecular pathways that induce and/or maintain DATPs are incompletely understood. Here we show that the bifunctional kinase/RNase-IRE1 alpha-a central mediator of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress is a critical promoter of DATP abundance and function. Administration of a nanomolar-potent, monoselective kinase inhibitor of IRE1 alpha (KIRA8)-or conditional epithelial IRE1 alpha gene knockout-both reduce DATP cell number and fibrosis in the bleomycin model, indicating that IRE1 alpha cell-autonomously promotes transition into the DATP state. IRE1 alpha enhances the profibrotic phenotype of DATPs since KIRA8 decreases expression of integrin alpha v beta 6, a key activator of transforming growth factor beta (TGF-beta) in pulmonary fibrosis, corresponding to decreased TGF-beta-induced gene expression in the epithelium and decreased collagen accumulation around DATPs. Furthermore, IRE1 alpha regulates DNA damage response (DDR) signaling, previously shown to promote the DATP phenotype, as IRE1 alpha loss-of-function decreases H2AX phosphorylation, Cdkn1 alpha (p21) expression, and DDRassociated secretory gene expression. Finally, KIRA8 treatment increases the differentiation of Krt19(CreERT2)-lineage-traced DATPs into type 1 alveolar epithelial cells after bleomycin injury, indicating that relief from IRE1 alpha signaling enables DATPs to exit the transitional state. Thus, IRE1 alpha coordinates a network of stress pathways that conspire to entrap injured cells in the DATP state. Pharmacological blockade of IRE1 alpha signaling helps resolve the DATP state, thereby ameliorating fibrosis and promoting salutary lung regeneration.