IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis
IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis
Abstract Idiopathic pulmonary fibrosis (IPF) is a disease of progressive interstitial fibrosis, which leads to severe debilitation, respiratory failure, and death. In IPF, environmental exposures interact with genetic risk factors to engender critical patho-etiological events in lung epithelial cells, including endoplasmic reticulum (ER) stress and TGFβ signaling, but the interactions between these disparate pathways are not well understood. We previously showed that kinase inhibitors of the IRE1α bifunctional kinase/RNase—a central mediator of the unfolded protein response (UPR) to ER stress—protected mice from bleomycin-induced pulmonary fibrosis. Here we show that a nanomolar-potent, mono-selective kinase inhibitor of IRE1α (KIRA8) decreases ER-stress induced TGFβ signaling and the senescence-associated secretory phenotype (SASP) in the lung epithelium after bleomycin exposure. A recently-described subset of “damage-associated transient progenitors” (DATPs) display IRE1α-regulated pathological gene signatures that are quelled by KIRA8, in vivo. After injury, these cells uniquely express integrin αvβ6, a key activator of TGFβ in pulmonary fibrosis. KIRA8 inhibition of IRE1α decreases both DATP number and Itgb6 expression in remaining cells, with a decrease in local collagen accumulation. Single-cell RNA sequencing from IPF lungs revealed an analogous Itgb6+ cell population that may also be regulated by IRE1α. These findings suggest that lung epithelial progenitor cells sit at the center of the fibrotic niche, and IRE1α signaling locks them into a dysfunctional state that establishes and perpetuates pathological fibrosis.
Backes Bradley J.、Thamsen Maike、Brumwell Alexis、Downey Michael S.、Papa Feroz R.、Chapman Harold A.、Sheppard Dean、Wenger Talia A.、Kathiriya Jaymin、Auyeung Vincent C.
Lung Biology Center, University of California||Department of Medicine, University of CaliforniaLung Biology Center, University of California||Department of Medicine, University of California||Quantitative Biosciences Institute (QBI) and Diabetes Center, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Department of Medicine, University of California||Cardiovascular Research Institute, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Lung Biology Center, University of California||Department of Medicine, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Lung Biology Center, University of California||Department of Medicine, University of California||Quantitative Biosciences Institute (QBI) and Diabetes Center, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Department of Medicine, University of California||Cardiovascular Research Institute, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Lung Biology Center, University of California||Department of Medicine, University of California||Cardiovascular Research Institute, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Lung Biology Center, University of California||Department of Medicine, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Department of Medicine, University of California||Cardiovascular Research Institute, University of CaliforniaDivision of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California||Lung Biology Center, University of California||Department of Medicine, University of California
基础医学内科学分子生物学
Backes Bradley J.,Thamsen Maike,Brumwell Alexis,Downey Michael S.,Papa Feroz R.,Chapman Harold A.,Sheppard Dean,Wenger Talia A.,Kathiriya Jaymin,Auyeung Vincent C..IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2021.09.16.460705.点此复制
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