Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

Aging is among the most important risk factors for the development of pulmonary fibrosis. Inappropriate or prolonged activation of the integrated stress response has been implicated in the pathobiology of both aging and pulmonary fibrosis. We found that a small molecule that relieves translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity pulmonary fibrosis in young and old mice. We demonstrate that severe fibrosis in old mice was associated with increased number of pathogenic monocyte-derived alveolar macrophages. Using transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased recruitment of pathogenic monocyte-derived alveolar macrophages. Thus our data suggest that inhibition of the integrated stress response in the lung epithelium can ameliorate pulmonary fibrosis by preventing the recruitment of monocyte-derived alveolar macrophages. Tissue-resident alveolar macrophages and monocyte-derived alveolar macrophages were sorted by flow cytometry from 2 months- and 18 months-old C57BL/6J mice naive and 28 days after administration of asbestos. RNA-seq libraries were prepared using NEBNext Ultra RNA Library Prep Kit with polyA enrichment and sequenced on Illumina NextSeq500 instrument.