Myeloid Ferritin Heavy Chain Regulates Macrophage Response to Kidney Injury by Modulating Synuclein-α and Ferroptosis

Background: Acute kidney injury and its progression to chronic kidney disease, are increasingly recognized as a continuum of insults culminating in significant adverse clinical sequelae. Macrophages comprise a heterogenous population with remarkable phenotypic plasticity essential for orchestrating injury responses and regulating iron homeostasis. Ferritin heavy chain (FtH), the principal intracellular iron storage protein endowed with intrinsic ferroxidase activity, catalyzes the oxidation of ferrous iron (Fe2+) to its more stable ferric state (Fe3+). Given FtH’s paramount role in dictating macrophage iron homeostasis, we sought to delineate the mechanisms by which FtH governs kidney iron trafficking in both health and disease. Methods: Utilizing myeloid-specific FtH knockout mice (FtHΔ/Δ) we employed various methodologies including bulk and single cell-RNA sequencing, real-time PCR, Western blotting, flow cytometry, mass spectrometry, and immunohistochemistry to establish the functional significance of myeloid FtH in kidney disease. Results: Synuclein-α (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion. Following kidney injury, FtHΔ/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 and markers of oxidative stress, as well as significant iron deposition in kidney tissues. This iron buildup in FtHΔ/Δ kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction. Conclusion: 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 insights provide a novel conceptual paradigm, wherein immune-mediated iron metabolism intersects with tissue injury, offering therapeutic targets that could concurrently mitigate kidney disease progression and its potential propagation to the brain, highlighting a possible mechanistic bridge to Parkinson’s disease. Funding: NIDDK Support