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PDE10A Inhibition Disrupts Lipid Droplet Formation and Sensitizes Macrophages to Ferroptosis after LPS treatment
Bradford C Berk1,2, Jinmin Zhang3, Chia George Hsu3,4
1Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Abstract:
Ferroptosis, an iron-dependent form of cell death, plays a key role in various diseases, but its impact on immune cells, particularly macrophages, remains unclear. This study explores how macrophage activation influences susceptibility to ferroptosis, focusing on lipopolysaccharide (LPS) and other inflammatory signals. We found that LPS priming enhanced resistance to ferroptosis in bone marrow-derived macrophages (BMDMs), as shown by reduced morphological changes, lower LDH release, and diminished cell death in real-time assays. Similar effects were observed with Zymosan A and TNF-α. Importantly, LPS-induced ferroptosis resistance was independent of stress response pathways like Nrf2 signaling. Instead, lipid droplet accumulation, driven by LPS, was central to this resistance. PDE10A inhibition reversed LPS-induced ferroptosis and reduced lipid droplet formation. LPS did not confer similar resistance in non-macrophage cell types, underscoring the macrophage-specific nature of this response. These findings highlight potential therapeutic targets for inflammatory diseases.
Insights
Inflammation, triggered by lipopolysaccharide (LPS), protects macrophages from ferroptosis, a cell death pathway. This resistance is linked to lipid droplet accumulation, offering new therapeutic targets for inflammatory diseases.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Ferroptosis, an iron-dependent cell death, is implicated in diseases.
- The role of macrophage activation in ferroptosis remains largely unknown.
Purpose of the Study:
- To investigate how macrophage activation influences ferroptosis susceptibility.
- To identify mechanisms underlying ferroptosis resistance in activated macrophages.
Main Methods:
- Utilized bone marrow-derived macrophages (BMDMs) and various inflammatory stimuli (LPS, Zymosan A, TNF-α).
- Assessed ferroptosis using morphological changes, lactate dehydrogenase (LDH) release, and real-time cell death assays.
- Investigated the role of lipid droplet accumulation and Nrf2 signaling pathways.
- Examined the effect of PDE10A inhibition on ferroptosis.
Main Results:
- LPS priming significantly enhanced resistance to ferroptosis in BMDMs.
- This resistance was associated with increased lipid droplet accumulation, not Nrf2 activation.
- Zymosan A and TNF-α also conferred ferroptosis resistance.
- PDE10A inhibition reversed LPS-induced ferroptosis resistance and reduced lipid droplets.
- Ferroptosis resistance was specific to macrophages.
Conclusions:
- Macrophage activation by inflammatory signals like LPS confers resistance to ferroptosis.
- Lipid droplet accumulation is a key mechanism driving this resistance.
- Targeting PDE10A may represent a therapeutic strategy for ferroptosis-related inflammatory conditions.
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