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Ferroptosis is involved in PGPS-induced otitis media in C57BL/6 mice
Bin Yan1,2, Daoli Xie1, Yuancheng Wu1
1Hearing and Speech Rehabilitation Institute, College of Special Education, Binzhou Medical University, Yantai, China.
Abstract:
Otitis media (OM) is a common disease that can cause hearing loss in children. Currently, the main clinical treatment for OM is antibiotics, but the overuse of antibiotics might lead to bacterial resistance, which is a worldwide public health challenge. Studying the pathogenesis of OM will help us develop new effective treatments. Ferroptosis is one type of programmed cell death characterized by the occurrence of lipid peroxidation driven by iron ions. Many studies have shown that ferroptosis is associated with infectious diseases. It is presently unclear whether ferroptosis is involved in the pathogenesis of OM. In this study, we explored the relationship between ferroptosis and OM by PGPS-induced OM in C57BL/6 mice and treating the induced OM with ferroptosis inhibitors deferoxamine (DFO), Ferrostatin-1 (Fer-1), and Liperoxstatin-1 (Lip-1). We examined the expression of ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (Cox2), glutathione peroxidase 4 (GPX4) protein as well as lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The results showed that in PGPS-induced OM model mice, several ferroptosis-related proteins including ACSL4 and Cox2 were up-regulated compared to mice treated with saline. Meanwhile, a ferroptosis-related protein GPX4 was down-regulated upon PGPS treatment. The DFO treatment in PGPS-inoculated mice effectively inhibited the development of OM. The inhibitors treatment caused a significant decrease in the expression of ACSL4, Cox2, 4 HNE, MDA, reduction in free iron. Meanwhile, the ferroptosis inhibitors treatment caused increase in the expression of inflammation-related factors tumor necrosis factor-α (TNF-α) and antioxidant protein GPX4. Our results suggest that there is a crosstalk between ferroptosis signaling pathway and the pathogenesis of OM. Ferroptosis inhibition can alleviate PGPS-induced OM.
Insights
Ferroptosis, a cell death process, is involved in otitis media (OM) pathogenesis. Inhibiting ferroptosis effectively reduced OM symptoms and inflammation in a mouse model, offering new treatment avenues.
Area of Science:
- Cell Biology
- Immunology
- Otolaryngology
Background:
- Otitis media (OM) is a common childhood disease often treated with antibiotics, raising concerns about bacterial resistance.
- Understanding OM pathogenesis is crucial for developing alternative treatments.
- Ferroptosis, a form of programmed cell death involving lipid peroxidation, is linked to infectious diseases, but its role in OM is unknown.
Purpose of the Study:
- To investigate the potential involvement of ferroptosis in the pathogenesis of otitis media.
- To evaluate the therapeutic effect of ferroptosis inhibitors on a mouse model of OM.
Main Methods:
- An otitis media model was induced in C57BL/6 mice using PGPS (Pneumococcal Pneumolysin).
- Mice were treated with ferroptosis inhibitors: deferoxamine (DFO), Ferrostatin-1 (Fer-1), and Liperoxstatin-1 (Lip-1).
- Expression of ferroptosis markers (ACSL4, Cox2, GPX4) and lipid peroxidation products (4-HNE, MDA) were analyzed.
Main Results:
- PGPS-induced OM mice showed increased ACSL4 and Cox2, and decreased GPX4 expression, indicating ferroptosis activation.
- Ferroptosis inhibitors significantly reduced OM severity, decreased ACSL4, Cox2, 4-HNE, MDA levels, and free iron.
- Inhibitor treatment also increased TNF-α and GPX4 expression, suggesting a modulation of inflammation and oxidative stress.
Conclusions:
- Ferroptosis signaling pathway is implicated in the pathogenesis of otitis media.
- Inhibition of ferroptosis demonstrates a therapeutic potential for alleviating OM.
- This study highlights ferroptosis as a novel target for otitis media treatment.
