Center for DAMP Biology, Third Affiliated Hospital of Guangzhou Medical University, Guangdong, China.
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.
Autophagy. 2022 Sep;18(9):2036-2049. doi: 10.1080/15548627.2021.2008692. Epub 2021 Dec 29.
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.
铁死亡是一种炎症细胞死亡形式，其关键介质仍不清楚。在这里，我们报告说，蛋白聚糖decorin（DCN）是由正在发生铁死亡的细胞释放的，然后作为警报信号触发先天和适应性免疫反应。铁死亡过程中 DCN 的早期释放是一个涉及分泌巨自噬/自噬和溶酶体胞吐的主动过程。一旦释放，细胞外的 DCN 与巨噬细胞上的晚期糖基化终产物特异性受体（AGER）结合，以 NFKB/NF-κB 依赖性方式触发促炎细胞因子的产生。DCN-AGER 轴的药理学和遗传学抑制可预防铁死亡相关的急性胰腺炎，并限制铁死亡癌细胞诱导肿瘤保护免疫反应的能力。因此，DCN 是铁死亡炎症和免疫后果的重要介质。
