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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. [ABSTRACT FROM AUTHOR]

Sepsis, a life-threatening condition resulting from a dysregulated response to pathogen infection, poses a significant challenge in clinical management. Here, we report a novel role for the autophagy receptor NCOA4 in the pathogenesis of sepsis. Activated macrophages and monocytes secrete NCOA4, which acts as a mediator of septic death in mice. Mechanistically, lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria, induces NCOA4 secretion through autophagy-dependent lysosomal exocytosis mediated by ATG5 and MCOLN1. Moreover, bacterial infection with E. coli or S. enterica leads to passive release of NCOA4 during GSDMD-mediated pyroptosis. Upon release, extracellular NCOA4 triggers the activation of the proinflammatory transcription factor NFKB/NF-κB by promoting the degradation of NFKBIA/IκB molecules. This process is dependent on the pattern recognition receptor AGER, rather than TLR4. In vivo studies employing endotoxemia and polymicrobial sepsis mouse models reveal that a monoclonal neutralizing antibody targeting NCOA4 or AGER delays animal death, protects against organ damage, and attenuates systemic inflammation. Furthermore, elevated plasma NCOA4 levels in septic patients, particularly in non-survivors, correlate positively with the sequential organ failure assessment score and concentrations of lactate and proinflammatory mediators, such as TNF, IL1B, IL6, and HMGB1. These findings demonstrate a previously unrecognized role of extracellular NCOA4 in inflammation, suggesting it as a potential therapeutic target for severe infectious diseases. Abbreviation: BMDMs: bone marrow-derived macrophages; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; ELISA: enzyme-linked immunosorbent assay; LPS: lipopolysaccharide; NO: nitric oxide; SOFA: sequential organ failure assessment. [ABSTRACT FROM AUTHOR]