Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12

被引：24

作者：

Tan, Jiangning ^{[1
,2
]}

Tedrow, John R. ^{[1
,2
]}

Nouraie, Mehdi ^{[1
,2
]}

Dutta, Justin A. ^{[1
,2
]}

Miller, David T. ^{[1
,2
]}

Li, Xiaoyun ^{[1
,2
]}

Yu, Shibing ^{[1
,2
]}

Chu, Yanxia ^{[1
,2
]}

Juan-Guardela, Brenda ^{[3
]}

Kaminski, Naftali ^{[3
]}

Ramani, Kritika ^{[4
]}

Biswas, Partha S. ^{[4
]}

Zhang, Yingze ^{[1
,2
]}

Kass, Daniel J. ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Dorothy P & Richard P Simmons Ctr Interstitial Lu, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA

[3] Yale Univ, Sect Pulm Crit Care & Sleep Med, Dept Internal Med, New Haven, CT 06520 USA

[4] Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, 930 Scaife Hall, Pittsburgh, PA 15261 USA

来源：

JOURNAL OF IMMUNOLOGY | 2017年 / 198卷 / 06期

基金：

美国国家卫生研究院;

关键词：

IDIOPATHIC PULMONARY-FIBROSIS; REGULATORY T-CELLS; GENE-EXPRESSION; OSTEOBLAST DIFFERENTIATION; TRANSCRIPTION FACTOR; FIBROBLASTS; GROWTH; MINERALIZATION; PATHOGENESIS; ACTIVATION;

D O I：

10.4049/jimmunol.1600610

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 in COL1A(2+) 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-kappa B 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.

引用

页码：2269 / 2285

页数：17

共 65 条

[1] X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis [J].