Immune-regulatory functions of atypical chemokine receptors in inflammatory renal diseases - Fibrosis-limiting role of ACKR2

慢性肾脏疾病（CKD）发展为肾功能不全是肾脏病学的一个关键问题。急性或慢性损伤肾组织再生受限导致的肾素损失导致纤维化重塑作为一种不适应的愈合反应发生。除了最初的急性或持续性慢性肾损伤外，诱导炎症的程度决定了是否发生恢复或持续的组织损伤和纤维化。因此，限制急性肾损伤或慢性肾脏疾病的炎症反应对于减少进行性实质损失和纤维化组织重塑，从而防止CKD进展至关重要。非典型趋化因子受体2 (ACKR2)，以前称为D6，不像经典趋化因子受体那样诱导G蛋白介导的白细胞活化和白细胞浸润到组织中。相反，它结合炎症趋化因子，内化这些趋化因子，并诱导它们在细胞内降解。这导致局部趋化因子水平降低和白细胞浸润减少。通过限制局部炎症，ACKR2可能对急性或慢性肾脏疾病中炎症组织损伤的解决至关重要，允许结构和功能恢复，从而防止CKD进展。与这一假设相一致，我们之前的研究得到了grant VI 231/3-1的支持，表明ACKR2限制了进行性自体肾毒性血清肾炎（慢性肾小球肾炎模型）和单侧肾缺血-再灌注-损伤后恢复期的肾脏炎症。在这两种模型中，ackr2缺陷敲除小鼠均表现出肾损伤加重，伴有更严重的炎症，最有趣的是更广泛的纤维化组织重塑。在这个项目中，我们现在想要在三种临床相关的慢性肾脏疾病小鼠模型中证明ACKR2的抗炎和抗纤维化功能，即慢性草酸肾病、糖尿病肾病和狼疮肾炎。这项工作应该确定ACKR2作为阻止CKD进展的潜在治疗靶点。此外，我们想要表征ACKR2在肾脏疾病中抗纤维化特性的机制。这可能是局部炎症减少后的间接影响，但ACK2的趋化因子清除活性也可能直接减少导致肾纤维化的骨髓源性纤维细胞的肾浸润。为此，我们将进行体外研究，并创建骨髓嵌合小鼠，以研究ACKR2在骨髓源性细胞（白细胞和纤维细胞）或实质细胞中表达的室特异性功能。ackr2缺陷小鼠的不良炎症表型将在实质ackr2缺乏和白细胞中趋化因子受体表达缺失的骨髓嵌合体中进一步研究，这将逆转ackr2缺陷小鼠中趋化因子配体水平改变的影响。

The progression of chronic kidney disease (CKD) to renal insufficiency is a key problem in nephrology. Nephron loss due to limited regeneration of acutely or chronically injured renal tissue leads to fibrotic remodeling occurring as a maladaptive healing response. Next to the initial acute or persistent chronic renal injury the extent of induced inflammation determines whether recovery or ongoing tissue damage and fibrosis occur. Therefore, limiting inflammatory responses in acute kidney injury or chronic renal disease is essential to reduce progressive parenchymal loss and fibrotic tissue remodeling, and thus preventing CKD progression.The atypical chemokine receptor 2 (ACKR2), formerly known as D6, does not induce G protein-mediated activation of leukocytes and leukocyte infiltration into tissues as classical chemokine receptors do. Instead, it binds inflammatory chemokines, internalizes these, and induces their intracellular degradation. This leads to reduced local chemokine levels and reduced leukocyte infiltration. By limiting local inflammation ACKR2 may critically contribute to the resolution of inflammatory tissue injury in acute or chronic renal disease, allowing structural and functional recovery and thus preventing CKD progression. In line with this hypothesis, our previous work supported by grant VI 231/3-1 demonstrated that ACKR2 limits renal inflammation in progressive autologous nephrotoxic serum nephritis, a model of chronic glomerulonephritis, and in the recovery phase after unilateral renal ischemia-reperfusion-injury. In both models Ackr2-deficient knockout mice showed increased renal injury, accompanied by more severe inflammation and most interestingly more extensive fibrotic tissue remodelling.In the proposed project we now want to demonstrate an anti-inflammatory and anti-fibrotic function of ACKR2 in three clinically relevant murine models of chronic renal disease, i.e chronic oxalate nephropathy, diabetic nephropathy and lupus nephritis. This work should identify ACKR2 as a potential therapeutic target to halt CKD progression. Moreover, we want to characterize mechanisms of the anti-fibrotic properties of ACKR2 in renal disease. These could be an indirect effect following reduced local inflammation, but chemokine scavenging activity of ACK2 may also directly reduce renal infiltration of bone marrow-derived fibrocytes which contribute to renal fibrosis. For this, we will perform in vitro studies and create bone marrow-chimeric mice to investigate compartment specific functions of ACKR2 expressed either in bone marrow-derived cells (leukocytes and fibrocytes) or parenchymal cells. Adverse inflammatory phenotypes in ACKR2-deficient mice will be further investigated in bone marrow-chimeras with parenchymal ACKR2-deficiency and absent expression of chemokine receptors in leukocytes, which should reverse effects of altered chemokine ligand levels in ACKR2-deficient mice.