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Myeloid FtH Regulates Macrophage Response to Kidney Injury by Modulating Snca and Ferroptosis
Abstract:
This study explored the role of myeloid ferritin heavy chain (FtH) in coordinating kidney iron trafficking in health and disease. Synuclein-α (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion (FtH Δ/Δ ). Following kidney injury, FtH Δ/Δ mice showed worsened kidney function. Transcriptome analysis revealed coupling of FtH deficiency with ferroptosis activation, a regulated cell death associated with iron accumulation. Adverse effects of ferroptosis were evidenced by upregulation of ferroptosis-related genes, increased oxidative stress markers, and significant iron deposition in kidney tissues. This iron buildup in FtH Δ/Δ kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction. Mechanistically, we establish that monomeric Snca functions as a ferrireductase catalyst, intensifying oxidative stress and triggering ferroptosis. Additionally, Snca accumulates in kidney diseases distinguished by leukocyte expansion across species. These findings position myeloid FtH as a pivotal orchestrator of the FtH-Snca-Spic axis driving macrophage reprogramming and kidney injury.
Highlights:
Myeloid FtH deficiency drives kidney injury via activation of ferroptosisMΦ FtH deficiency induces Snca, linking iron dysregulation to MΦ function and response to kidney injuryFerrireductase activity of monomeric Snca augments oxidative stress, promoting lipid peroxidation and ferroptosis.
In Brief:
MΦ FtH modulates Snca and Spic to coordinate the injury response, linking iron trafficking to ferroptosis-induced kidney injury.
Insights
Myeloid ferritin heavy chain (FtH) deficiency worsens kidney injury by promoting iron buildup and ferroptosis. This occurs through Synuclein-α (Snca) activating oxidative stress and macrophage reprogramming, linking iron dysregulation to kidney disease.
Area of Science:
- Nephrology
- Cell Biology
- Immunology
Background:
- Ferritin heavy chain (FtH) plays a role in iron regulation.
- Iron dysregulation is implicated in kidney disease pathogenesis.
- Macrophage function is critical in kidney injury response.
Purpose of the Study:
- To investigate the role of myeloid FtH in kidney iron trafficking.
- To understand the mechanisms linking FtH deficiency to kidney injury.
- To explore the involvement of Synuclein-α (Snca) in this process.
Main Methods:
- Utilized FtH-deficient mice (FtH Δ/Δ) and kidney injury models.
- Performed transcriptome analysis to identify gene expression changes.
- Assessed markers of oxidative stress, ferroptosis, and iron deposition.
- Investigated the ferrireductase activity of Snca.
Main Results:
- Myeloid FtH deficiency exacerbated kidney injury and worsened kidney function.
- FtH deficiency led to ferroptosis activation, characterized by increased oxidative stress and iron deposition.
- Macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction, contributed to iron buildup.
- Monomeric Snca acted as a ferrireductase, intensifying oxidative stress and promoting ferroptosis.
Conclusions:
- Myeloid FtH is crucial for coordinating kidney iron trafficking and preventing injury.
- The FtH-Snca-Spic axis drives macrophage reprogramming and ferroptosis in kidney disease.
- Targeting this axis may offer therapeutic strategies for kidney injury.
