Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis.
Fibrosis
Pulmonology
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
23 05 2022
23 05 2022
Historique:
received:
04
08
2020
accepted:
12
04
2022
pubmed:
15
4
2022
medline:
25
5
2022
entrez:
14
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35420997
pii: 142984
doi: 10.1172/jci.insight.142984
pmc: PMC9220956
doi:
pii:
Substances chimiques
Homeodomain Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL129795
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139897
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157100
Pays : United States
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