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Molecular Mechanisms of Apoptotic Cell Phagocytosis by Macrophages

巨噬细胞吞噬凋亡细胞的分子机制

基本信息

批准号：
14599006
负责人：
TANAKA Masato
金额：
$ 2.3万
依托单位：
RIKEN (The Institute of Physical and Chemical Research) (2003)Osaka University (2002)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14599006/
关键词：
apoptosis macrophage phagocytosis MFG-E8 SHPS-1 Del-1 SHPS-1

项目摘要

Macrophages and dendritic cells recognize not only microorgaisms from outside of the body, but also dying self-cells to eliminate them by engulfment. This phenomenon prevents the release of potentially harmful or immunogenic intracellular materials from dying cells. We have previously shown that milk fat globule-EGF-factor 8 (MFG-E8) is involved in apoptotic cell phagocytosis by phagocytes. MFG-E8 specifically binds to PS exposed on apoptotic cells via C-terminal factor VIII-homologous domains. When MFG-E8 is engaged by apoptotic cells, it binds to α_vβ_3 integrin expressed in phagocytes via a N-terminal EGF-like domain, and promotes the phagocytosis of apoptotic cells. These results indicated that MFG-E8 secreted from activated macrophages binds to apoptotic cells, and brings them to phagocytes for engulfment. We found that one mouse macrophage cell line (BAM3) engulfed apoptotic thymocytes, but not apoptotic WR19L cells, a T-cell line. Monoclonal antibodies that inhibited the phagocy … More tosis of apoptotic thymocytes by BAM3 were identified. Purification of the antigen revealed that it was SHPS-1. CD47,the ligand for SHPS-1,was expressed in mouse thymocytes, but not in WR19L. When WR19L was transformed with CD47,the transformants, after induction of apoptosis, could be phagocytosed by BAM3. The WR19L transformants expressing CD47 were more efficiently engulfed in vivo by splenic dendritic cells than the parental WR19L. Masking of the phosphatidylserine exposed on apoptotic thymocytes inhibited the engulfment. Whereas, the anti-SHPS-1 mAb inhibited not only the engulfment but also the binding of apoptotic cells to phagocytes. These results indicate that macrophages require CD47 and phosphatidylserine on,apoptotic cells for engulfment, and suggest that the interaction between CD47 and SHPS-1 works as a tethering step in the phagocytosis. We also found that Del-1 is highly homologous to MFG-E8,and has a similar function in terms of promoting phagocytosis of apoptotic cells. Less

巨噬细胞和树突状细胞不仅识别来自体外的微生物，还识别垂死的自身细胞，并通过吞噬来消除它们。这种现象防止潜在有害或免疫原性细胞内物质从垂死细胞中释放。我们以前已经表明，乳脂球EGF因子8（MFG-E8）参与吞噬细胞的凋亡细胞吞噬作用。MFG-E8通过C末端因子VIII同源结构域特异性结合凋亡细胞上暴露的PS。当MFG-E8与凋亡细胞结合时，它通过N端EGF样结构域与吞噬细胞表达的α vβ 3整合素结合，促进凋亡细胞的吞噬作用。这些结果表明，从活化的巨噬细胞分泌的MFG-E8与凋亡细胞结合，并将它们带到吞噬细胞中进行吞噬。我们发现一种小鼠巨噬细胞系（BAM 3）吞噬凋亡的胸腺细胞，但不吞噬凋亡的WR 19 L细胞，一种T细胞系。抑制吞噬的单克隆抗体 ...更多信息用BAM 3鉴定凋亡胸腺细胞的凋亡。纯化抗原表明其为SHPS-1。SHPS-1的配体CD 47在小鼠胸腺细胞中表达，但在WR 19 L中不表达。当WR 19 L用CD 47转化时，转化子在诱导凋亡后可以被BAM 3吞噬。表达CD 47的WR 19 L转化体在体内比亲本WR 19 L更有效地被脾树突状细胞吞噬。掩蔽暴露在凋亡胸腺细胞上的磷脂酰丝氨酸抑制了吞噬。而抗SHPS-1单抗不仅抑制吞噬作用，而且抑制凋亡细胞与吞噬细胞的结合。这些结果表明，巨噬细胞需要CD 47和磷脂酰丝氨酸对凋亡细胞进行吞噬，并表明CD 47和SHPS-1之间的相互作用作为吞噬作用中的束缚步骤。我们还发现Del-1与MFG-E8高度同源，并且在促进凋亡细胞的吞噬方面具有相似的功能。少