| Summary: | Summary: Aerobic organisms need to maintain cellular redox homeostasis. Glutathione peroxidase-4 (Gpx4) has the unique ability to protect cells against lipid peroxidation. Here, we show that Gpx4 is absolutely required to prevent ferroptosis during development, maintenance, and responses of innate-like B cells, namely, the B1 and marginal zone (MZ) B cells. In contrast, Gpx4 is dispensable for the development, germinal center reactions, and antibody responses of follicular B2 cells. Mechanistically, we show increased lipid metabolism and sensitivity to lipid peroxidation and ferroptosis in B1 and MZ B cells compared to follicular B2 cells, consistent with the requirement of Gpx4 in innate-like B cells. This high sensitivity to ferroptosis of innate-like B cells may be used to therapeutically target Gpx4 in certain forms of B cell malignancies involving B1 cells. : Muri et al. demonstrate that B1 and marginal zone (MZ) B cells but not follicular (Fo) B2 cells require Gpx4 during homeostasis and antibody responses. Mechanistically, B1 and MZ B cells display increased lipid metabolism, sensitivity to lipid peroxidation, and ferroptosis in comparison to Fo B cells. Keywords: Gpx4, ferroptosis, lipid ROS, fatty-acid metabolism, B cell immunometabolism, B1 cells, marginal zone B cells, redox system, glutathione
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