Fractalkine (CX3CL1) and Its Receptor CX3CR1: A Promising Therapeutic Target in Chronic Kidney Disease?

Abstract

Innate immune cells are key contributors to kidney inflammation and fibrosis. Infiltration of the renal parenchyma by innate immune cells is governed by multiple signalling pathways. Since the discovery of the chemokine fractalkine (CX3CL1) and its receptor, CX3CR1 over twenty years ago, a wealth of evidence has emerged linking CX3CL1-CX3CR1 signalling to renal pathologies in both acute and chronic kidney diseases (CKD). However, despite the extent of data indicating a pathogenic role for this pathway in kidney disease and its complications, no human trials of targeted therapeutic agents have been reported. Although acute autoimmune kidney disease is often successfully treated with immunomodulatory medications, there is a notable lack of treatment options for patients with progressive fibrotic CKD. In this article we revisit the CX3CL1-CX3CR1 axis and its functional roles. Furthermore we review the accumulating evidence that CX3CL1-CX3CR1 interactions mediate important events in the intra-renal pathophysiology of CKD progression, particularly via recruitment of innate immune cells into the kidney. We also consider the role that systemic activation of the CX3CL1-CX3CR1 axis in renal disease contributes to CKD-associated cardiovascular disease. Based on this evidence, we highlight the potential for therapies targeting CX3CL1 or CX3CR1 to benefit people living with CKD.

Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases

“…In fact, motility and metastasis of pancreatic adenocarcinoma cells can be inhibited with the CX3CR1 specific inhibitor JMS-17-2 [71]. In addition, in acute autoimmune kidney disease and in chronic kidney disease (CKD), CX3CR1 appears to be of major importance in the recruitment of immune cells and in the processes leading to macrophage-mediated fibrosis of the kidney [72]. Some small molecules and specific CX3CR1-inhibiting antibodies are being assayed in animal models and clinical trials to treat multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, or CKD [72].…”

“…In addition, in acute autoimmune kidney disease and in chronic kidney disease (CKD), CX3CR1 appears to be of major importance in the recruitment of immune cells and in the processes leading to macrophage-mediated fibrosis of the kidney [72]. Some small molecules and specific CX3CR1-inhibiting antibodies are being assayed in animal models and clinical trials to treat multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, or CKD [72]. This knowledge reinforces the idea that targeting of CCR6 and CX3CR1 PDZ-interactions to modulate such immune-related disorders is an interesting topic to be explored.…”

Identification of Hub Genes Correlated with the Initiation and Development in Chronic Kidney Disease via Bioinformatics Analysis

“…The enhanced CX3CL1/CX3CR1 axis is observed in the kidney of human and animal CKD models and contributes to infiltration of immune cells and the progression of fibrosis. However, inhibition of CX3CL1/CX3CR1 axis by deficiency or antagonists suppresses the progression of renal fibrosis and impairment in CKD [13] . Increased CCL17 was observed in CKD patients along with decrease of renal function [10] .…”

CX3CR1 deficiency exacerbates immune-mediated hepatitis by increasing NF-κB-mediated cytokine production in macrophage and T cell

“…2 The chemokine C-X3C motif ligand 1 (CX3CL1) and its sole receptor, C-X3C motif receptor 1 (CX3CR1), are involved in the recruitment of monocytes/macrophages and T cells and play critical roles in many diseases. [3][4][5] In patients with severe acute hepatic B hepatitis, the expression CX3CR1 deficiency exacerbates immune-mediated hepatitis by increasing NF-κB-mediated cytokine production in macrophage and T cell of CX3CL1 and CX3CR1 are upregulated. 6 However, the role of the CX3CL1/CX3CR1 axis in immune-mediated hepatic injury remains unclear.…”