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

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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.