Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

Satoshi Watanabe; Nikolay S. Markov; Ziyan Lu; Raul Piseaux Aillon; Saul Soberanes; Constance E. Runyan; Ziyou Ren; Rogan A. Grant; Mariana Maciel; Hiam Abdala-Valencia; Yuliya Politanska; Kiwon Nam; Lango Sichizya; Hermon G. Kihshen; Nikita Joshi; Alexandra C. McQuattie-Pimentel; Katherine A. Gruner; Manu Jain; Jacob I. Sznajder; Richard I. Morimoto; Paul Andrew Reyfman; Cara J. Gottardi; G. R.Scott Budinger; Alexander V. Misharin

doi:10.1073/pnas.2101100118

Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

Satoshi Watanabe, Nikolay S. Markov, Ziyan Lu, Raul Piseaux Aillon, Saul Soberanes, Constance E. Runyan, Ziyou Ren, Rogan A. Grant, Mariana Maciel, Hiam Abdala-Valencia, Yuliya Politanska, Kiwon Nam, Lango Sichizya, Hermon G. Kihshen, Nikita Joshi, Alexandra C. McQuattie-Pimentel, Katherine A. Gruner, Manu Jain, Jacob I. Sznajder, Richard I. MorimotoPaul Andrew Reyfman, Cara J. Gottardi, G. R.Scott Budinger^*, Alexander V. Misharin

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy,we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

Original language	English (US)
Article number	e2101100118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	20
DOIs	https://doi.org/10.1073/pnas.2101100118
State	Published - May 18 2021

Funding

ACKNOWLEDGMENTS. This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Fein-berg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University’s Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111-01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964. This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University's Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111- 01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964.

Keywords

Fibrosis
ISRIB
Proteostasis

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2101100118

Cite this

Watanabe, S., Markov, N. S., Lu, Z., Aillon, R. P., Soberanes, S., Runyan, C. E., Ren, Z., Grant, R. A., Maciel, M., Abdala-Valencia, H., Politanska, Y., Nam, K., Sichizya, L., Kihshen, H. G., Joshi, N., McQuattie-Pimentel, A. C., Gruner, K. A., Jain, M., Sznajder, J. I., ... Misharin, A. V. (2021). Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America, 118(20), Article e2101100118. https://doi.org/10.1073/pnas.2101100118

@article{7b92096b4437467eb6700c516960c3c0,

title = "Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis",

abstract = "Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy,we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.",

keywords = "Fibrosis, ISRIB, Proteostasis",

author = "Satoshi Watanabe and Markov, {Nikolay S.} and Ziyan Lu and Aillon, {Raul Piseaux} and Saul Soberanes and Runyan, {Constance E.} and Ziyou Ren and Grant, {Rogan A.} and Mariana Maciel and Hiam Abdala-Valencia and Yuliya Politanska and Kiwon Nam and Lango Sichizya and Kihshen, {Hermon G.} and Nikita Joshi and McQuattie-Pimentel, {Alexandra C.} and Gruner, {Katherine A.} and Manu Jain and Sznajder, {Jacob I.} and Morimoto, {Richard I.} and Reyfman, {Paul Andrew} and Gottardi, {Cara J.} and Budinger, {G. R.Scott} and Misharin, {Alexander V.}",

note = "Funding Information: ACKNOWLEDGMENTS. This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Fein-berg{\textquoteright}s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University{\textquoteright}s Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111-01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964. Funding Information: This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University's Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111- 01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

year = "2021",

month = may,

day = "18",

doi = "10.1073/pnas.2101100118",

language = "English (US)",

volume = "118",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "20",

}

Watanabe, S, Markov, NS, Lu, Z, Aillon, RP, Soberanes, S, Runyan, CE, Ren, Z, Grant, RA, Maciel, M, Abdala-Valencia, H, Politanska, Y, Nam, K, Sichizya, L, Kihshen, HG, Joshi, N, McQuattie-Pimentel, AC, Gruner, KA, Jain, M , Sznajder, JI , Morimoto, RI, Reyfman, PA, Gottardi, CJ , Budinger, GRS & Misharin, AV 2021, 'Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 20, e2101100118. https://doi.org/10.1073/pnas.2101100118

TY - JOUR

T1 - Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

AU - Watanabe, Satoshi

AU - Markov, Nikolay S.

AU - Lu, Ziyan

AU - Aillon, Raul Piseaux

AU - Soberanes, Saul

AU - Runyan, Constance E.

AU - Ren, Ziyou

AU - Grant, Rogan A.

AU - Maciel, Mariana

AU - Abdala-Valencia, Hiam

AU - Politanska, Yuliya

AU - Nam, Kiwon

AU - Sichizya, Lango

AU - Kihshen, Hermon G.

AU - Joshi, Nikita

AU - McQuattie-Pimentel, Alexandra C.

AU - Gruner, Katherine A.

AU - Jain, Manu

AU - Sznajder, Jacob I.

AU - Morimoto, Richard I.

AU - Reyfman, Paul Andrew

AU - Gottardi, Cara J.

AU - Budinger, G. R.Scott

AU - Misharin, Alexander V.

N1 - Funding Information: ACKNOWLEDGMENTS. This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Fein-berg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University’s Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111-01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964. Funding Information: This work used services from Northwestern University RHLCCC Flow Cytometry Facility, Center for Advanced Microscopy, and Mouse Histology and Phenotyping Laboratory, which are supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope acquired through the support of NIH 1S10OD010398-01. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computing Cluster (Genomic Nodes on Quest), which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. S.W. is supported by MSD Life Science Foundation, Public Interest Incorporated Foundation, and the David W. Cugell and Christina Enroth-Cugell Fellowship Program at Northwestern University. P.A.R. is supported by Northwestern University's Lung Sciences Training Program 5T32HL076139-13, 1F32HL136111- 01A1, and NIH K08HL146943; Parker B. Francis Fellowship; and the American Thoracic Society Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. R.A.G. is supported by T32AG020506-18 and F31AG071225. M.J. is supported by The Veterans Administration grant BX000201. C.J.G. is supported by NIH grants HL134800 and GM129312 and a research grant from Boehringer Ingelheim Pharmaceuticals, Inc. G.R.S.B. is supported by NIH grants ES013995, HL071643, and AG049665 and The Veterans Administration grant BX000201. A.V.M. is supported by NIH grants HL135124, HL153312, AG049665, and AI135964. Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.

PY - 2021/5/18

Y1 - 2021/5/18

N2 - Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy,we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

AB - Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy,we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

KW - Fibrosis

KW - ISRIB

KW - Proteostasis

UR - http://www.scopus.com/inward/record.url?scp=85105769474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85105769474&partnerID=8YFLogxK

U2 - 10.1073/pnas.2101100118

DO - 10.1073/pnas.2101100118

M3 - Article

C2 - 33972447

AN - SCOPUS:85105769474

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 20

M1 - e2101100118

ER -

Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this