权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Physiological roles of apoptotic cell clearance

凋亡细胞清除的生理作用

基本信息

批准号：
16601004
负责人：
TANAKA Masato
金额：
$ 2.43万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16601004/
关键词：
macrophage apoptosis phagocytosis autoantibody type II epithelial cells ARDS 死細胞貪食 MFG-E8

项目摘要

Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. We found that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited the phagocytosis of apoptotic cells by a wide variety of phagocytes. When intravenously injected into mice, the D89E protein induced the production of auto-antibodies including anti-phospholipids antibodies and anti-nuclear antibodies. The production of auto-antibodies was enhanced by the co-injection of syngeneic apoptotic thymocytes. Following the induction of auto-antibody production by D89E, the treated mice showed a long-term elevation of the titer for auto-antibodies, and developed IgG deposition in the gromeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to auto-antibody production.We generated transgenic mice in which type II lung epithelial cells as well as macrophages were transiently ablated. Human diphtheria toxin receptor was expressed under the control of the lysozyme M gene promoter in the mice. When diphtheria toxin was administrated to the mice, they suffered from acute lung injury, and died within 4 days. Type II cells as well as alveolar macrophages were deleted in the mice treated with diphtheria toxin. The amount of surfactant proteins A and B in bronchoalveolar lavage fluid was greatly reduced in the diphtheria toxin-treated transgenic mice. When the bone marrow from wild-type mice was transplanted into the irradiated transgenic mice, the alveolar macrophages became resistant to diphtheria toxin, but the mice still suffered from acute lung injury. These results indicated that ablation of type II cells caused lethal acute respiratory distress in association with the reduced amount of surfactant proteins.

乳脂球egf -因子8 （MFG-E8）由活化的巨噬细胞和未成熟的树突状细胞分泌，连接凋亡细胞和吞噬细胞，促进凋亡细胞的吞噬作用。我们发现MFG-E8突变体D89E携带RGD基序点突变，抑制多种吞噬细胞对凋亡细胞的吞噬作用。当静脉注射到小鼠体内时，D89E蛋白诱导自身抗体的产生，包括抗磷脂抗体和抗核抗体。共注射同种凋亡胸腺细胞可增强自身抗体的产生。在D89E诱导自身抗体产生后，治疗小鼠的自身抗体滴度长期升高，并在小囊中形成IgG沉积。这些结果表明凋亡细胞吞噬功能受损导致自身抗体的产生。我们产生了转基因小鼠，其中II型肺上皮细胞和巨噬细胞被短暂消融。人白喉毒素受体在溶菌酶M基因启动子控制下在小鼠体内表达。白喉毒素给药后小鼠出现急性肺损伤，4天内死亡。在白喉毒素处理的小鼠中，II型细胞和肺泡巨噬细胞被删除。经白喉毒素处理的转基因小鼠支气管肺泡灌洗液中表面活性剂蛋白A和B的含量明显降低。将野生型小鼠骨髓移植到辐照转基因小鼠体内后，肺泡巨噬细胞对白喉毒素产生了抗性，但小鼠仍出现急性肺损伤。这些结果表明，II型细胞消融引起致命性急性呼吸窘迫与表面活性剂蛋白的减少有关。