Molecular and Immunometabolic Landscape of Erythrophagocytosis-induced Ferroptosis

Erythrocytes constitute the main cell type of the blood, contain the majority of the iron in the body, and have a high turnover rate. Erythrocyte death and subsequent degradation lead to ferroptosis. In this context, modifications of the erythrocyte plasma membrane lipidome are instrumental to the phenomenon. Thus, phospholipase A2, phospholipase D, lysophospholipase D, sphingomyelinase, ceramidase, and sphingosine kinase acting together orchestrate a major membrane structural rearrangement, leading to phosphatidylserine exposure, reduced deformability, and band 3 clustering. Band 3 clustering may lead to antibody and complement opsonization, CD47 conformational change, and phosphatidylserine exposure. Meanwhile, arginine, glutamine, and adenosine metabolism modulate the anti-oxidant capacity of erythrocytes, thus impacting phosphatidylserine exposure and chemokine release. Metabolism-induced augmented erythrophagocytosis accompanied by insufficient upregulation of heme oxygenase-1 and iron retention due to inflammatory signals lead to iron-dependent lipid peroxidation. Neudesin, interleukin 33, interleukin 18, TNF-α, interleukin 6, prostaglandins, epinephrin, itaconate, and hepcidin influence the capacity of the macrophage to manipulate iron. BACH1, NRF2, and SPIC are the main transcription factors implicated in the regulation of the expression of heme oxygenase-1 and ferroportin. Insufficient adaptation of the metabolism of the cell to neutralize lipid peroxides leads to iron-dependent programmed lytic death, called ferroptosis. As a result of ferroptosis, damage-associated molecular patterns and lipid peroxides are released, activating the neighboring immune cells and triggering inflammation. Erythrophagocytosis-induced ferroptosis has been recognized as a main mechanism eliciting the metabolism dysfunction associated with steatohepatitis, atherosclerosis, uremia, and other pathogenic states. A better understanding of the molecular mechanisms implicated in the process could bring forward potential novel therapeutic targets. In this mini-review, the current literature is summarized with regard to the immunometabolic mechanisms that mediate erythrophagocytosis-induced ferroptosis and inflammation.