Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12.
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the accumulation of apoptosis-resistant fibroblasts in the lung. We have previously shown that high expression of the transcription factor Twist1 may explain this prosurvival phenotype in vitro. However, this observation has never been tested in vivo. We found that loss of Twist1 inCOL1A2+cells led to increased fibrosis characterized by very significant accumulation of T cells and bone marrow-derived matrix-producing cells. We found that Twist1-null cells expressed high levels of the T cell chemoattractant CXCL12. In vitro, we found that the loss of Twist1 in IPF lung fibroblasts increased expression of CXCL12 downstream of increased expression of the noncanonical NF-κB transcription factor RelB. Finally, blockade of CXCL12 with AMD3100 attenuated the exaggerated fibrosis observed in Twist1-null mice. Transcriptomic analysis of 134 IPF patients revealed that low expression of Twist1 was characterized by enrichment of T cell pathways. In conclusion, loss of Twist1 in collagen-producing cells led to increased bleomycin-induced pulmonary fibrosis, which is mediated by increased expression of CXCL12. Twist1 expression is associated with dysregulation of T cells in IPF patients. Twist1 may shape the IPF phenotype and regulate inflammation in fibrotic lung injury.
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Jiangning
J
Tan
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
John R
0000-0002-4236-4430
JR
Tedrow
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Mehdi
M
Nouraie
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Justin A
JA
Dutta
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
David T
0000-0002-7223-3925
DT
Miller
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Xiaoyun
X
Li
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Shibing
S
Yu
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Yanxia
Y
Chu
Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06520; and.
Brenda
B
Juan-Guardela
Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06520; and.
Naftali
N
Kaminski
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Kritika
K
Ramani
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
Partha S
PS
Biswas
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
Yingze
0000-0001-6947-2901
Y
Zhang
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213; kassd2@upmc.edu.
Daniel J
0000-0001-6597-7830
DJ
Kass
D000368:Aged; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D008168:Lung / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D054377:Chemokine CXCL12; D024042:Collagen Type I; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051879:Twist-Related Protein 1; D001761:Bleomycin