Journal article
Wnt5a/Ca2+ signaling regulates silica-induced ferroptosis in mouse macrophages by altering ER stress-mediated redox balance
Toxicology (Amsterdam), Vol.490, 153514
05/15/2023
DOI: 10.1016/j.tox.2023.153514
PMID: 37075931
Abstract
Silicosis is a chronic pulmonary disease characterized by diffuse fibrosis of lung caused by the deposition of silica dust (SiO2). The inhaled silica-induced oxidative stress, ROS production and macrophage ferroptosis are key drivers of the pathological process of silicosis. However, mechanisms that involved in the silica-induced macrophage ferroptosis and its contributions to pathogenesis of silicosis remain elusive. In the present study, we showed that silica induced murine macrophage ferroptosis, accompanied by elevation of inflammatory responses, Wnt5a/Ca2+ signaling activation, and concurrent increase of endoplasmic reticulum (ER) stress and mitochondrial redox imbalance in vitro and vivo. Mechanistic study further demonstrated that Wnt5a/Ca2+ signaling played a key role in silica-induced macrophage ferroptosis by modulating ER stress and mitochondrial redox balance. The presence of Wnt5a/Ca2+ signaling ligand Wnt5a protein increased the silica-induced macrophage ferroptosis by activating ER-mediated immunoglobulin heavy chain binding protein (Bip)-C/EBP homology protein (Chop) signaling cascade, reducing the expression of negative regulators of ferroptosis, glutathione peroxidase 4 (Gpx4) and solute carrier family 7 member 11 (Slc7a11), subsequentially increasing lipid peroxidation. The pharmacologic inhibition of Wnt5a signaling or block of calcium flow exhibited an opposite effect to Wnt5a, resulted in the reduction of ferroptosis and the expression of Bip-Chop signaling molecules. These findings were further corroborated by the addition of ferroptosis activator Erastin or inhibitor ferrostatin-1. These results provide a mechanism by which silica activates Wnt5a/Ca2+ signaling and ER stress, sequentially leads to redox imbalance and ferroptosis in mouse macrophage cells.
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Details
- Title: Subtitle
- Wnt5a/Ca2+ signaling regulates silica-induced ferroptosis in mouse macrophages by altering ER stress-mediated redox balance
- Creators
- Jia Ma - Ningxia UniversityJiaqi Wang - Ningxia Medical UniversityChenjie Ma - Ningxia UniversityQian Cai - Ningxia UniversityShuang Wu - Ningxia UniversityWenfeng Hu - Ningxia UniversityJiali Yang - Ningxia UniversityJing Xue - Ningxia UniversityJuan Chen - Ningxia Medical UniversityXiaoming Liu - Ningxia University
- Resource Type
- Journal article
- Publication Details
- Toxicology (Amsterdam), Vol.490, 153514
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.tox.2023.153514
- PMID
- 37075931
- ISSN
- 0300-483X
- eISSN
- 1879-3185
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 32070863, 32260174, 81760004
- Language
- English
- Date published
- 05/15/2023
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984398207302771
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