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Role of GRK in engulfment of apoptotic cells

GRK 在吞噬凋亡细胞中的作用

基本信息

批准号：
23659043
负责人：
KUROSE Hitoshi
金额：
$ 2.41万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

项目摘要

In the body, apoptotic cells are rapidly removed by the cells such as macrophages and dendritic cells. Otherwise, inefficient removal of apoptotic cells results in transition of apoptotic cells to late necrotic cells and leakage of their own intracellular contents. This leakage causes appearance of autoantibody and induction of inflammation, leading to collapse of the body’ s homeostasis. The removal of apoptotic cells is called as engulfment. So far, there are three engulfment pathways: Abl/Abi, ELMO/DOCK180, and ABC/MFGF10/GULF/dynamin signaling pathways. In this study, we revealed that G protein-coupled receptor (GPCR) kinase 6 (GRK6), which is believed to regulate GPCR function, was involved in engulfment. This pathway was independent of three known pathways. GRK6 bound Ezrin/Radixin/Moesin (ERM) and ultimately activated Rac1 that is indispensable for engulfment. GRK6-mediated engulfment was also observed in endogenous macrophages. In GRK6 knockout (GRK6-KO) mice, systemic lupus erythematosus (SLE), one of autoimmune diseases, -like symptoms such as increased anti-double strand DNA antibody in the plasma and deposition of immunocomplex in the kidney were observed. Furthermore, we observed abnormalities in the spleen. In white pulp of the spleen that removes apoptotic B cells, the number of ungulfed apoptotic cells in GRK6-KO mice was higher than that in wild type mice. In red pulp of the spleen that removes aged red blood cells, we observed the increased iron deposition due to impaired removal of aged red blood cells. These results suggest that GRK6 is a mediator of engulf apoptotic cells, and impaired function of GRK6 results in autoimmune disease and affects recycling of red blood cells. This study reveals that GRK has a new role in the cells andbody, although GRK is generally accepted as a mediator of GPCR regulation.

在体内，凋亡细胞被细胞如巨噬细胞和树突状细胞迅速清除。否则，凋亡细胞的无效去除导致凋亡细胞向晚期坏死细胞的转变和其自身细胞内内容物的渗漏。这种泄漏导致自身抗体的出现和炎症的诱导，导致身体的稳态崩溃。凋亡细胞的清除被称为吞噬。到目前为止，有三种吞噬途径：Abl/Abi、埃尔莫/DOCK 180和ABC/MFGF 10/GULF/dynamin信号通路。在这项研究中，我们发现，G蛋白偶联受体（GPCR）激酶6（GRK 6），这被认为是调节GPCR功能，参与吞噬。该途径独立于三种已知途径。GRK 6结合Ezrin/Radixin/Moesin（ERM）并最终激活对于吞噬不可或缺的Rac 1。在内源性巨噬细胞中也观察到GRK 6介导的吞噬。在GRK 6基因敲除（GRK 6-KO）小鼠中，观察到系统性红斑狼疮（SLE）（自身免疫性疾病之一）样症状，如血浆中抗双链DNA抗体增加和免疫复合物在肾脏中沉积。此外，我们观察到脾脏异常。在去除凋亡B细胞的脾脏的白色髓中，GRK 6-KO小鼠中的有蹄凋亡细胞的数量高于野生型小鼠。在去除老化红细胞的脾脏红髓中，我们观察到由于老化红细胞的去除受损而导致的铁沉积增加。这些结果表明GRK 6是吞噬凋亡细胞的介导者，GRK 6的功能受损导致自身免疫性疾病并影响红细胞的再循环。本研究揭示了GRK在细胞和机体中的新作用，尽管GRK通常被认为是GPCR调节的介导剂。