Myeloid Ferritin Heavy Chain Regulates Macrophage Differentiation towards Iron Recycling Phenotype in CKD

Background: Chronic kidney disease (CKD) is a worldwide public health problem affecting ~850 million people. Dysregulation in iron metabolism is a hallmark of advanced CKD. Myeloid cells, particularly macrophages (MΦ), play a crucial role in establishing the delicate balance of iron homeostasis. Ferritin, a spherical shell composed of heavy (FtH) and light (FtL) chains, is paramount in maintenance of this process. Our overarching hypothesis is that myeloid FtH orchestrates iron distribution and regulates MΦ plasticity under injurious/inflammatory conditions through controlling Spic expression. Methods: To investigate the role of myeloid FtH in relation to kidney iron metabolism, mice deficient in FtH in the myeloid compartment (FtHLysmΔ/Δ) were generated. Experiments were carried out using bulk RNA sequencing, single cell RNA sequencing, real-time PCR, western blot, flow cytometry, immunohistochemistry. Results: Using unbiased transcriptome analysis, significant upregulation of Spic, a transcription factor that selectively controls the development of iron recycling MΦ (Fe-MΦ) was observed in kidneys of FtHLysmΔ/Δ mice following iron administration. This observation was further validated by other markers expressed by this subset of MΦ and was accompanied by higher degree of tubular iron deposition when compared to their wild-type counterparts (FtHfl/fl). Moreover, we observed marked induction of Spic in different kidney injury models including ischemia-reperfusion, aristolochic acid, and sepsis mediated kidney injury. Notably, Fe-MΦ are responsible for the resolution stage of the injury and inflammation. Functional significance of myeloid FtH was validated by worse kidney outcomes as evidenced by higher serum creatinine, increased fibrosis, and leukocyte expansion. Conclusion: Our findings suggest a potential contribution of myeloid FtH to calibrate the iron recycling MΦ phenotype during kidney injury and resolution however, the functional significance of spic in the context of CKD remain to be elucidated. Funding: NIDDK Support