Resetting proteostasis with ISRIB prevents pulmonary fibrosis

Abstract

Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts.Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

“…However, the treatment with ISRIB was neuroprotective without inducing any adverse effect on the pancreas, but it only partially restored global protein translation, as compared with GSK2606414 [ 159 ]. Recently, in an ALS rodent model, the inhibition of PERK signaling with ISRIB, but not with GSK2606414, significantly enhanced the neuronal survival via a partial inhibition of the translation imposed by PERK and a reduction in IRE1-dependent signaling [ 175 ]. In addition to neurodegenerative diseases, ISRIB was recently found to inhibit stress response signaling in the aging lung epithelium leading to decreased apoptosis and reduced recruitment of pathogenic monocyte-derived alveolar macrophages [ 176 ].…”

Lung injury induces alveolar type 2 cell hypertrophy and polyploidy with implications for repair and regeneration

“…In this way, eIF2a phosphorylation and its diverse downstream consequences comprise the ISR (33,34). A small molecule integrated stress response inhibitor, ISRIB, was found to render cells insensitive to eIF2α phosphorylation, thereby restoring translation capacity to normalize cell function (35)(36)(37) and limit a range of tissue pathologies in murine disease models (38)(39)(40)(41)(42). Our team recently discovered that ISRIB improves fibrosis in murine models by limiting abundance of AT2 cells stalled at the AT2-to-AT1 transition state (17).…”