Abstract
During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A2. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.
Highlights
These authors contributed : Xiang Luo, Hai-Biao Gong, HuaYing GaoEdited by H
To establish that ferroptosis was a form of cell death distinct from apoptosis, HL60 cells were treated with RSL3 or STS for 6 h in the absence or presence of ferroptosis inhibitors, ferrostatin-1 (Fer1) or deferoxamine (DFO)
We explored the critical players that facilitate recognition and clearance of ferroptotic cells by macrophages
Summary
More than 100 billion short-lived or damaged cells are recycled in the human body every day. While it is recognized that many oncogenic pathways render cancer cells extremely susceptible to ferroptosis [11], there is evidence suggesting that ferroptosis could be induced as an intrinsic antitumor mechanism that propagates through cells and tissues This has key implications for cancer therapy since it may be possible to eliminate large groups of malignant cells in the tumor niche by triggering propagative death through ferroptosis [12]. Recent studies identified RSL3, an inhibitor of glutathione peroxidase-4 (GPX4) [6], as an efficient inducer of ferroptotic cell death in cancer cells [13] This has led to the understanding that ferroptosis is largely a specialized death program caused by insufficiency of GPX4, the only known enzyme that can reduce lipid hydroperoxides within biological membranes [14,15,16]. We identified TLR2 as a potential candidate receptor for SAPE-OOH and established a concept of SAPE-OOH and TLR2 as critical players for engulfment of ferroptotic cells
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