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.
Highlights
Innate immune cells are key contributors to kidney inflammation and fibrosis
For the remainder of this article, we focus on subsequent evidence that CX3CL1 interaction with CX3CR1 is of distinct pathophysiological importance to the progression of fibrosis and impaired renal function in chronic kidney diseases (CKD)
This study provides strong evidence that upregulation of CX3CL1 by proximal tubular epithelial cells (PTEC) is a mechanism by which pro-fibrogenic dendritic cells (DCs) are recruited and retained in the renal parenchyma in CKD
Summary
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. Further work utilised in vitro analyses of murine renal tubular epithelial cell lines and demonstrated that these cells were capable of upregulating CX3CL1 expression and demonstrated increased chemotactic potency for peripheral blood mononuclear cells after stimulation with cytokines such as TNF-a, IL-1b or TGF-b [57] This animal study indicated that many of the functional effects of CX3CL1 demonstrated in more acute models of renal disease are relevant to CKD. In a different disease scenario, it has been demonstrated that CX3CR1-dependent mechanisms protect against acute kidney injury in sepsis [59] These studies, which indicate that there may be counterregulatory roles for CX3CR1-expressing myeloid cells during pro-fibrotic renal inflammation, must be taken into consideration when evaluating the clinical potential of CX3CR1 blockade in human CKD from diverse causes.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
