An Atlas of Ferroptosis-induced Secretomes promotes Macrophage priming

Cells undergoing regulated necrosis systemically communicate with the immune system via release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. While proteins with assigned DAMP and innate immune system function such as MIF, heat shock proteins (HSPs) and chaperonines were released from ferroptotic cells, this happened in the absence of bona fide inflammatory chemo- cytokines. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic enhanced LPS-induced cytokine production. These results define the spectrum of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.