Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2

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 un...

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Bibliographic Details
Published in:Cell death and differentiation 2021-06, Vol.28 (6), p.1971-1989
Main Authors: Luo, Xiang, Gong, Hai-Biao, Gao, Hua-Ying, Wu, Yan-Ping, Sun, Wan-Yang, Li, Zheng-Qiu, Wang, Guan, Liu, Bo, Liang, Lei, Kurihara, Hiroshi, Duan, Wen-Jun, Li, Yi-Fang, He, Rong-Rong
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cancer therapies
Cell death
Cell surface
Chinese medicine
Ferroptosis
Ferroptosis - genetics
Gene silencing
Homeostasis
Humans
Immune clearance
Laboratories
Lipid peroxidation
Lipids
Macrophages
Mammary gland
Mice
Phagocytes
Phagocytosis
Phagocytosis - genetics
Phosphatidylethanolamine
Phosphatidylethanolamines - metabolism
Phospholipase A2
Phospholipids
TLR2 protein
Toll-Like Receptor 2 - metabolism
Toll-like receptors
Tumor Microenvironment
Tumors
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Summary: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 A . 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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-00719-2