Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) s...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.142984 |
| _version_ | 1811329627172372480 |
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| author | Cory Wilson Tinne C.J. Mertens Pooja Shivshankar Weizen Bi Scott D. Collum Nancy Wareing Junsuk Ko Tingting Weng Ram P. Naikawadi Paul J. Wolters Pascal Maire Soma S.K. Jyothula Rajarajan A. Thandavarayan Dewei Ren Nathan D. Elrod Eric J. Wagner Howard J. Huang Burton F. Dickey Heide L. Ford Harry Karmouty-Quintana |
| author_facet | Cory Wilson Tinne C.J. Mertens Pooja Shivshankar Weizen Bi Scott D. Collum Nancy Wareing Junsuk Ko Tingting Weng Ram P. Naikawadi Paul J. Wolters Pascal Maire Soma S.K. Jyothula Rajarajan A. Thandavarayan Dewei Ren Nathan D. Elrod Eric J. Wagner Howard J. Huang Burton F. Dickey Heide L. Ford Harry Karmouty-Quintana |
| author_sort | Cory Wilson |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional coactivators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin-treated (BLM-treated) mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis, as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression, and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter–driven luciferase assay demonstrated direct binding of Six1 to the 5′-TCAGG-3′ consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis and providing a potentially novel pathway for targeting in IPF therapy. |
| first_indexed | 2024-04-13T15:48:14Z |
| format | Article |
| id | doaj.art-0b6befeecf974b68b90fc8fc86c89505 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T15:48:14Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0b6befeecf974b68b90fc8fc86c895052022-12-22T02:40:55ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-01710Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosisCory WilsonTinne C.J. MertensPooja ShivshankarWeizen BiScott D. CollumNancy WareingJunsuk KoTingting WengRam P. NaikawadiPaul J. WoltersPascal MaireSoma S.K. JyothulaRajarajan A. ThandavarayanDewei RenNathan D. ElrodEric J. WagnerHoward J. HuangBurton F. DickeyHeide L. FordHarry Karmouty-QuintanaIdiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional coactivators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin-treated (BLM-treated) mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis, as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression, and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter–driven luciferase assay demonstrated direct binding of Six1 to the 5′-TCAGG-3′ consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis and providing a potentially novel pathway for targeting in IPF therapy. https://doi.org/10.1172/jci.insight.142984Pulmonology |
| spellingShingle | Cory Wilson Tinne C.J. Mertens Pooja Shivshankar Weizen Bi Scott D. Collum Nancy Wareing Junsuk Ko Tingting Weng Ram P. Naikawadi Paul J. Wolters Pascal Maire Soma S.K. Jyothula Rajarajan A. Thandavarayan Dewei Ren Nathan D. Elrod Eric J. Wagner Howard J. Huang Burton F. Dickey Heide L. Ford Harry Karmouty-Quintana Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis JCI Insight Pulmonology |
| title | Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| title_full | Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| title_fullStr | Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| title_full_unstemmed | Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| title_short | Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| title_sort | sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis |
| topic | Pulmonology |
| url | https://doi.org/10.1172/jci.insight.142984 |
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