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，还识别死亡的自身细胞，通过吞噬将其消除。我们之前已经证明，乳脂球可以防止死亡细胞释放潜在有害或免疫原性的细胞内物质。 -EGF 因子 8 (MFG-E8) 参与吞噬细胞的凋亡细胞吞噬作用，MFG-E8 特异性结合暴露在外的 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中表达的 α_vβ_3 整合素结合，并促进凋亡细胞的吞噬作用。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我们发现一种小鼠巨噬细胞系 (BAM3) 吞噬凋亡的胸腺细胞，但不吞噬凋亡的 WR19L 细胞，这是一种通过 BAM3 抑制凋亡胸腺细胞吞噬的单克隆抗体。结果表明，SHPS-1 的配体 CD47 在小鼠体内表达。当WR19L用CD47转化时，在诱导细胞凋亡后，表达CD47的WR19L转化体在体内比亲代WR19L更有效地被脾树突状细胞吞噬。暴露在凋亡胸腺细胞上的磷脂酰丝氨酸抑制但抗 SHPS-1 mAb 不仅抑制吞噬细胞，还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 CD47 和磷脂酰丝氨酸来吞噬凋亡细胞，并表明 CD47 和吞噬细胞之间存在相互作用。 SHPS-1 在吞噬作用中充当束缚步骤我们还发现 Del-1 与 SHPS-1 高度同源。 MFG-E8，在促进凋亡细胞吞噬方面也有类似的功能。