Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2.
Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2.
复制标题
氧化磷脂酰乙醇胺通过与 TLR2 相互作用引导铁死亡细胞的吞噬作用
DOI：
10.1038/s41418-020-00719-2
复制
发表时间：
2021-06
影响因子：
12.4
通讯作者：
He RR
中科院分区：
文献类型：
--
作者：
Luo X;Gong HB;Gao HY;Wu YP;Sun WY;Li ZQ;Wang G;Liu B;Liang L;Kurihara H;Duan WJ;Li YF;He RR
在癌症治疗期间，死亡细胞的吞噬清除在免疫稳态中起着至关重要的作用。非凋亡形式的细胞死亡，铁凋亡，在肿瘤治疗中表现出非凡的潜力。然而，调节铁凋亡细胞吞噬的吞噬机制仍不清楚。在这里，我们建立了一个新的途径，从典型的机制不同，通过使用不同的铁凋亡模型引起的GPX 4功能障碍/缺陷的铁凋亡细胞的吞噬清除。我们鉴定了氧化磷脂，1-硬脂酰-2-15-HpETE-sn-甘油基-3-磷脂酰乙醇胺（SAPE-OOH），作为铁凋亡细胞表面的关键eat-me信号。用SAPE-OOH富集质膜增加了巨噬细胞对铁凋亡细胞的吞噬效率，这是一个被脂蛋白相关磷脂酶A2抑制的过程。配体钓鱼、脂质印迹和细胞热位移测定筛选并鉴定了TLR 2作为直接识别SAPE-OOH的膜受体，这通过TLR 2抑制剂和基因沉默研究进一步证实。铁凋亡的小鼠乳腺肿瘤模型验证了SAPE-OOH和TLR 2是体内铁凋亡细胞清除的关键参与者。总之，这项工作表明，铁凋亡细胞表面上的SAPE-OOH充当eat-me信号，并通过靶向巨噬细胞上的TLR 2来导航吞噬作用。
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.
登录
查看更多内容
ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
14.8
作者：
Gaschler MM;Andia AA;Liu H;Csuka JM;Hurlocker B;Vaiana CA;Heindel DW;Zuckerman DS;Bos PH;Reznik E;Ye LF;Tyurina YY;Lin AJ;Shchepinov MS;Chan AY;Peguero-Pereira E;Fomich MA;Daniels JD;Bekish AV;Shmanai VV;Kagan VE;Mahal LK;Woerpel KA;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
21.3
作者：
Ilina O;Gritsenko PG;Syga S;Lippoldt J;La Porta CAM;Chepizhko O;Grosser S;Vullings M;Bakker GJ;Starruß J;Bult P;Zapperi S;Käs JA;Deutsch A;Friedl P
通讯作者：
Friedl P
DOI：
10.1038/s41580-020-0262-8
发表时间：
2020-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Martire S;Banaszynski LA
通讯作者：
Banaszynski LA