HDAC3 promotes pulmonary fibrosis by activating NOTCH1 and STAT1 signaling and up-regulating inflammasome components AIM2 and ASC.

Abstract

BACKGROUND:

Pre-clinical studies suggest that pan-inhibitors for histone deacetylases (HDACs) may benefit the treatment of pulmonary fibrosis (PF). However, HDAC3-specific roles or mechanisms during PF development are poorly understood.

METHODS:

The expression of HDAC3 and the impacts of RGFP966, a selective HDAC3 inhibitor, were examined in a bleomycin-induced PF mouse model and in TGF-β-challenged MRC-5 cells. H&E and Masson staining were employed to reveal the pathological changes in lung; Western blot to assess expressions of biomarkers related to fibrosis and epithelial-mesenchymal transition (EMT), activations of Notch1 and signal transducer and activator of transcription 1 (STAT1) signaling, and levels of inflammasome components, absent in melanoma 2 (AIM2) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC); ELISA to measure productions of proinflammatory interleukin (IL)-1β and IL-18; cycloheximide chase assay and coimmunoprecipitation to monitor the protein stability and acetylation of Notch intracellular domain 1 (NICD1) and STAT1, respectively.

RESULTS:

HDAC3 was induced in in vitro and in vivo PF models, which was associated with elevated expressions of fibrosis-related biomarkers, EMT markers, and pro-inflammatory cytokines, activations of Notch1 and STAT1 signaling, and up-regulated inflammasome components, AIM2 and ASC. All the fibrotic phenotypes were potently inhibited by RGFP966, which boosted the acetylation of NICD1 and STAT1, accelerated the degradation of NICD1, and inhibited STAT1 phosphorylation. Overexpressing NICD1 or STAT1 restored the fibrotic phenotypes suppressed by RGFP966.

CONCLUSIONS:

HDAC3 promoted EMT, inflammation, and PF development by activating Notch1 and STAT1 signaling. Therefore, targeting HDAC3, Notch1 or STAT1 signaling may ameliorate PF development.

• Authors: Qing Zheng, Yao Lei, Shan Hui, Ming Tong, Lihui Liang
• Journal: Cytokine (Cytokine) Vol. 153 Pg. 155842 (05 2022) ISSN: 1096-0023 [Electronic] England
• PMID: 35306425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Aim2 protein, mouse
• DNA-Binding Proteins
• Inflammasomes
• STAT1 Transcription Factor
• Stat1 protein, mouse
• Histone Deacetylases

Topics

• Animals
• DNA-Binding Proteins (metabolism)
• Histone Deacetylases (metabolism)
• Inflammasomes (metabolism)
• Melanoma
• Mice
• Pulmonary Fibrosis (chemically induced)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction