TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF

Authors

Lan Wang
Wenyu Zhao
Cong Xia
Zhongzheng Li
Weiming Zhao
Kai Xu
Ningdan Wang
Hui Lian
Ivan O Rosas
Guoying Yu

Language

English

Publication Date

12-11-2022

Journal

International Journal of Molecular Sciences

DOI

10.3390/ijms232415705

PMID

36555349

PMCID

PMC9778945

PubMedCentral® Posted Date

12-11-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells. TRIB3 attenuated pulmonary fibrosis by negative regulation of ATF4, while TRIB3 expression markedly inhibited ATF4 promoter-driven transcription activity and down-regulated ATF4 expression. A co-culture system showed that TRIB3 is important to maintain the normal epithelial–mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis of TRIB3–ATF4 is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.

Keywords

Humans, Idiopathic Pulmonary Fibrosis, Fibrosis, Lung, Extracellular Matrix, Fibroblasts, Repressor Proteins, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Activating Transcription Factor 4, Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells. TRIB3 attenuated pulmonary fibrosis by negative regulation of ATF4, while TRIB3 expression markedly inhibited ATF4 promoter-driven transcription activity and down-regulated ATF4 expression. A co-culture system showed that TRIB3 is important to maintain the normal epithelial–mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis of TRIB3–ATF4 is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.

Published Open-Access

yes

Recommended Citation

Wang, Lan; Zhao, Wenyu; Xia, Cong; et al., "TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF" (2022). Faculty and Staff Publications. 4744.
https://digitalcommons.library.tmc.edu/baylor_docs/4744