DCN released from ferroptotic cells ignites AGER-dependent immune responses

Ferroptosis is a form of inflammatory cell death for which key mediators remain obscure. Here, we report that the proteoglycan decorin (DCN) is released by cells that are dying from ferroptosis and then acts as an alarm signal to trigger innate and adaptive immune responses. The early release of DCN during ferroptosis is an active process that involves secretory macroautophagy/autophagy and lysosomal exocytosis. Once released, extracellular DCN binds to the receptor advanced glycosylation end-product-specific receptor (AGER) on macrophages to trigger the production of pro-inflammatory cytokines in an NFKB/NF-κB-dependent manner. Pharmacological and genetic inhibition of the DCN-AGER axis protects against ferroptotic death-related acute pancreatitis and limits the capacity of ferroptotic cancer cells to induce a tumor-protective immune response. Thus, DCN is an essential mediator of the inflammatory and immune consequences of ferroptosis.