An atlas of ferroptosis-induced secretomes
Fatma Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Min Yang, Maria Nenchova, Emin Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T. Abdallah, Jan‐Wilm Lackmann, Christina M. Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt
Abstract
Cells undergoing regulated necrosis systemically communicate with the immune system via the 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. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. 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 supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.