Role of the CX₃CL1-CX₃CR1 axis in renal disease

Abstract

Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines are key drivers of this process. CX3CL1 (fractalkine) is one of two unique chemokines synthesized as a transmembrane protein which undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, CX3CR1, CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form, and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.

Decoding the Mechanism behind the Pathogenesis of the Focal Segmental Glomerulosclerosis

“…In accordance with our findings, a recent report elucidated that the activation of complement in kidney cells with increased generation of C3 contributes to the induced podocyte injury in primary membranous nephropathy [ 47 ]. The emerging studies of chemokines and chemokine receptors showed a distinct perspective on the chronic nephropathy pandemic [ 48 ]. Theoretically, chemokines majorly act as a chemoattractant to guide the migration of leukocytes and immune cells in the respective anatomical locations [ 49 ].…”

Transcriptional profile changes after treatment of ischemia reperfusion injury-induced kidney fibrosis with 18β-glycyrrhetinic acid

“…Pharmacological blockade of CCL2 or CCR2 have successfully entered clinical trials studying treatment of type 2 diabetes and nephropathy [ 36 , 37 ]. CX 3 CL1 is the only member of the CX 3 C superfamily [ 38 ], whose transmembrane region undergoes proteolytic cleavage to generate a soluble form as chemokine [ 39 ]. The study by Peng et al.…”

Immunosenescence: an unexplored role in glomerulonephritis

“…This receptor binds with its sole ligand, fractalkine, in both soluble or (membrane)-bound forms, and plays a crucial role in human pathophysiology as a chemokine and adhesion molecule. 66 It is involved in the early phase of vascular inflammation, chronic inflammatory diseases such as RA but also has regulatory functions. 16 Upregulation of this axis by angiotensin-II (AT-II) in the aorta and vascular smooth muscle cells of uremic mice promotes homing of T cells.…”

“…16,49,70,71 The high expression of CX3CR1 in senescent CD28 null CD4 + lymphocytes stimulates homing of these cells into the inflamed kidney perpetuating a positive feedback loop. 66 This property is shared with CD8 + T cells, NK and iNKT cells, cd T cells and mononuclear phagocytes such as activated macrophages and monocytes while B cells lack CX3CR1. 66 Recent data disclosed its role as kidneyspecific homing-receptor for cDC2, which recruit and regulate immune cells in glomerulonephritis.…”

“…66 This property is shared with CD8 + T cells, NK and iNKT cells, cd T cells and mononuclear phagocytes such as activated macrophages and monocytes while B cells lack CX3CR1. 66 Recent data disclosed its role as kidneyspecific homing-receptor for cDC2, which recruit and regulate immune cells in glomerulonephritis. 71,72 The proportion of CX3CR1 expressing T cells and serum concentration of fractalkine is increased in CKD.…”