Role of GRK in engulfment of apoptotic cells

在体内，凋亡细胞被巨噬细胞和树突状细胞等细胞迅速清除。否则，凋亡细胞的清除效率低下，导致凋亡细胞向晚期坏死细胞过渡，细胞内内容物渗漏。这种渗漏引起自身抗体的出现和炎症的诱导，导致体内稳态的崩溃。凋亡细胞的清除称为吞噬。目前，有三种吞噬通路：Abl/Abi、ELMO/DOCK180和ABC/MFGF10/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 （GRK6）参与了吞噬过程，据信它可以调节GPCR的功能。这个途径独立于三个已知的途径。GRK6结合Ezrin/Radixin/Moesin (ERM)，最终激活吞噬所必需的Rac1。在内源性巨噬细胞中也观察到grk6介导的吞噬。在GRK6基因敲除（GRK6- ko）小鼠中，观察到血浆中抗双链DNA抗体升高和肾脏中免疫复合物沉积等自身免疫性疾病之一系统性红斑狼疮（SLE）的症状。此外，我们还观察到脾脏的异常。在去除凋亡B细胞的脾脏白髓中，GRK6-KO小鼠未吞噬的凋亡细胞数量高于野生型小鼠。在去除衰老红细胞的脾红髓中，我们观察到由于衰老红细胞的去除受损而增加的铁沉积。这些结果表明GRK6是吞噬凋亡细胞的介质，GRK6功能受损导致自身免疫性疾病并影响红细胞的再循环。这项研究揭示了GRK在细胞和机体中具有新的作用，尽管GRK通常被认为是GPCR调控的中介。

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.