Identification of ZIP8-induced ferroptosis as a major type of cell death in monocytes under sepsis conditions

Abstract

Sepsis is a heterogenous syndrome with concurrent hyperinflammation and immune suppression. A prominent feature of immunosuppression during sepsis is the dysfunction and loss of monocytes; however, the major type of cell death contributing to this depletion, as well as its underlying molecular mechanisms, are yet to be identified. In this study, we confirmed the monocyte loss in septic patients based on a pooled gene expression data of periphery leukocytes. Using the collected reference gene sets from databases and published studies, we identified ferroptosis with a greater capacity to distinguish between sepsis and control samples than other cell death types. Further investigation on the molecular drivers, by a genetic algorithm-based feature selection and a weighted gene co-expression network analysis, revealed that zrt-/irt-like protein 8 (ZIP8), encoded by SLC39A8, was closely associated with ferroptosis of monocytes during sepsis. We validated the increase of ZIP8 of monocytes with in vivo and in vitro experiments. The in vitro studies also showed that downregulation of ZIP8 alleviated the lipopolysaccharide-induced lipid peroxidation, as well as restoring the reduction of GPX4, FTH1 and xCT. These findings suggest that ferroptosis might be a key factor in the loss of monocytes during sepsis, and that the heightened expression of ZIP8 may facilitate this progression.