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Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2025 | Viewed by 16589

Special Issue Editor

Prof. Dr. Dariusz Szukiewicz

E-Mail Website
Guest Editor
Department of Biophysics, Physiology and Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Chalubinskiego 5 (4th Floor), 02-004 Warsaw, Poland
Interests: inflammation; cytokine network; sirtuins; endothelial signaling; human placenta; stem cells; pathophysiology of diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fractalkine (FKN), also known as CX3CL1, is the only member of the chemokine family containing a three amino acid motif between the two cysteines (C-X-X-X-C) and a mucin-like domain. This chemokine is made up of 373 amino acids and is synthesized as a transmembrane molecule. Moreover, after cleavage by the TNFα-converting enzyme ADAM17, FKN can exist in a soluble form. Such peculiar structural characteristics of fractalkine go hand in hand with its unique functional properties, because FKN combines the features of a chemoattractant and an adhesion molecule. Both of these functions require the presence of a specific and sole FKN receptor, CX3C motif chemokine receptor 1 (CX3CR1), also known as G-protein coupled receptor 13 (GPR13). Considering that CX3CR1 expression was demonstrated on many different cells, including but not limited to monocytes, microglia and macrophages, dendritic cells, T cells, natural killer (NK) cells, vascular endothelial cells, smooth and skeletal muscle cells, neurons, hepatocytes, adipocytes, and endometrial cells, FKN signaling may be crucial in health and disease. FKN-CX3CR1 signaling exerts distinct functions in different tissue compartments, and may be involved in a wide spectrum of biological phenomena such as cell adhesion and chemotaxis, immune response, inflammation, apoptosis, implantation, angiogenesis, atherosclerosis, formation of endometriotic foci, neurotoxicity, or carcinogenesis.

This Special Issue is dedicated to all aspects of FKN signaling, including both physiological and pathologic conditions. It may be extremely interesting to present the reasons for recognizing the FKN-CX3CR1 signaling pathway as the main therapeutic target in a given disease.

When considering your submission, please keep in mind that IJMS is a journal of molecular science. However, submissions of clinical studies that include biomolecular experiments or pathological research with case sample data are welcome.

Prof. Dr. Dariusz Szukiewicz
Guest Editor

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Keywords

  • fractalkine
  • transmembrane fractalkine
  • soluble fractalkine
  • fractalkine receptor
  • CX3CL1-CX3CR1 signaling
  • inflammation
  • chemokine
  • cell adhesion
  • chemotaxis
  • immune response
  • angiogenesis
  • implantation
  • atherosclerosis
  • carcinogenesis

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Published Papers (8 papers)

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20 pages, 7469 KiB  
Article
Effects of Cerebrospinal Fluids from Alzheimer and Non-Alzheimer Patients on Neurons–Astrocytes–Microglia Co-Culture
by Matilda Iemmolo, Giulia Bivona, Tommaso Piccoli, Aldo Nicosia, Gabriella Schiera, Carlo Maria Di Liegro, Fabrizio Di Pietra and Giulio Ghersi
Int. J. Mol. Sci. 2024, 25(5), 2510; https://doi.org/10.3390/ijms25052510 - 21 Feb 2024
Cited by 2 | Viewed by 1989
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, characterized by the accumulation of β-amyloid plaques, tau tangles, neuroinflammation, and synaptic/neuronal loss, the latter being the strongest correlating factor with memory and cognitive impairment. Through an in vitro study on a neurons–astrocytes–microglia [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, characterized by the accumulation of β-amyloid plaques, tau tangles, neuroinflammation, and synaptic/neuronal loss, the latter being the strongest correlating factor with memory and cognitive impairment. Through an in vitro study on a neurons–astrocytes–microglia (NAM) co-culture system, we analyzed the effects of cerebrospinal fluid (CSF) samples from AD and non-AD patients (other neurodegenerative pathologies). Treatment with CSF from AD patients showed a loss of neurofilaments and spheroids, suggesting the presence of elements including CX3CL1 (soluble form), destabilizing the neurofilaments, cellular adhesion processes, and intercellular contacts. The NAM co-cultures were analyzed in immunofluorescence assays for several markers related to AD, such as through zymography, where the expression of proteolytic enzymes was quantified both in cell extracts and the co-cultures’ conditioned medium (CM). Through qRT-PCR assays, several genes involved in the formation of β-amyloid plaque, in phosphorylation of tau, and in inflammation pathways and MMP expression were investigated. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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Review

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15 pages, 259 KiB  
Review
CX3CL1 Regulation of Gliosis in Neuroinflammatory and Neuroprotective Processes
by Irene L. Gutiérrez, David Martín-Hernández, Karina S. MacDowell, Borja García-Bueno, Javier R. Caso, Juan C. Leza and José L. M. Madrigal
Int. J. Mol. Sci. 2025, 26(3), 959; https://doi.org/10.3390/ijms26030959 - 23 Jan 2025
Viewed by 972
Abstract
Among the different chemokines, C-X3-C motif chemokine ligand 1 or CX3CL1, also named fractalkine, is one of the most interesting due to its characteristics, including its unique structure, not shared by any other chemokine, and its ability to function both in a membrane-bound [...] Read more.
Among the different chemokines, C-X3-C motif chemokine ligand 1 or CX3CL1, also named fractalkine, is one of the most interesting due to its characteristics, including its unique structure, not shared by any other chemokine, and its ability to function both in a membrane-bound form and in a soluble form, among others. However, undoubtedly, its most relevant characteristic from the neuroscientific point of view is its role as a messenger used by neurons to communicate with microglia. The study of the interaction between both cell types and the key role that CX3CL1 seems to play has facilitated the identification of CX3CL1 as a crucial modulator of microglial activation and a promising target in the fight against neuroinflammation. As a result, numerous studies have contributed to elucidate the involvement of CX3CL1 and its specific receptor CCX3CR1 in the progression of different neuroinflammatory and neurodegenerative processes, with Alzheimer’s and Parkinson’s diseases being the most studied ones. However, the different animal and cellular models used to reproduce the pathological conditions to be analyzed, as well as the difficulties inherent to studies performed on human samples, have hindered the collection of compatible results in many cases. In this review, we summarize some of the most relevant data describing the alterations found for the CX3CL1/CX3CR1 signaling axis in different neurodegenerative conditions in which neuroinflammation is known to play a relevant role. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
18 pages, 1166 KiB  
Review
The Role of Fractalkine in Diabetic Retinopathy: Pathophysiology and Clinical Implications
by Cheng-Yung Lee and Chang-Hao Yang
Int. J. Mol. Sci. 2025, 26(1), 378; https://doi.org/10.3390/ijms26010378 - 4 Jan 2025
Cited by 1 | Viewed by 1128
Abstract
Diabetic retinopathy (DR) is a complication of diabetes, characterized by progressive microvascular dysfunction that can result in vision loss. Chronic hyperglycemia drives oxidative stress, endothelial dysfunction, and inflammation, leading to retinal damage and complications such as neovascularization. Current treatments, including anti-VEGF agents, have [...] Read more.
Diabetic retinopathy (DR) is a complication of diabetes, characterized by progressive microvascular dysfunction that can result in vision loss. Chronic hyperglycemia drives oxidative stress, endothelial dysfunction, and inflammation, leading to retinal damage and complications such as neovascularization. Current treatments, including anti-VEGF agents, have limitations, necessitating the exploration of alternative therapeutic strategies. Fractalkine (CX3CL1), a chemokine with dual roles as a membrane-bound adhesion molecule and a soluble chemoattractant, has emerged as a potential therapeutic target. Its receptor, CX3CR1, is expressed on immune cells and mediates processes such as immune cell recruitment and microglial activation through intracellular signaling pathways. In DR, soluble fractalkine plays critical roles in retinal inflammation, angiogenesis, and neuroprotection, balancing tissue damage and repair. In DR, elevated fractalkine levels are associated with retinal inflammation and endothelial dysfunction. Experimental studies suggest that fractalkine deficiency exacerbates the severity of diabetic retinopathy (DR), whereas exogenous fractalkine appears to reduce inflammation, oxidative stress, and neuronal damage. However, its role in pathological angiogenesis within DR remains unclear and warrants further investigation. Preclinical evidence indicates that fractalkine may hold therapeutic potential, particularly in mitigating tissue injury and inflammation associated with early-stage DR. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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13 pages, 654 KiB  
Review
The Role of the CX3CR1-CX3CL1 Axis in Respiratory Syncytial Virus Infection and the Triggered Immune Response
by Selma Rivas-Fuentes, Alfonso Salgado-Aguayo, Teresa Santos-Mendoza and Edgar Sevilla-Reyes
Int. J. Mol. Sci. 2024, 25(18), 9800; https://doi.org/10.3390/ijms25189800 - 11 Sep 2024
Cited by 1 | Viewed by 1738
Abstract
Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and older adults. This virus is responsible for one-third of pneumonia deaths in the pediatric population; however, there [...] Read more.
Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and older adults. This virus is responsible for one-third of pneumonia deaths in the pediatric population; however, there are currently only a few effective vaccines. A better understanding of the RSV–host relationship at the molecular level may lead to a more effective management of RSV-related symptoms. The fractalkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and diverse immune cells. RSV G protein binds to the CX3CR1 receptor via a highly conserved amino acid motif (CX3C motif), which is also present in CX3CL1. The CX3CL1-CX3CR1 axis is involved in the activation and infiltration of immune cells into the infected lung. The presence of the RSV G protein alters the natural functions of the CX3CR1-CX3CL1 axis and modifies the host’s immune response, an aspects that need to be considered in the development of an efficient vaccine and specific pharmacological treatment. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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20 pages, 1549 KiB  
Review
Fractalkine in Health and Disease
by Claudia Rodriguez, Luisa Chocarro, Miriam Echaide, Karina Ausin, David Escors and Grazyna Kochan
Int. J. Mol. Sci. 2024, 25(15), 8007; https://doi.org/10.3390/ijms25158007 - 23 Jul 2024
Cited by 3 | Viewed by 2042
Abstract
CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The [...] Read more.
CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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21 pages, 1410 KiB  
Review
Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy
by Mateusz Wątroba, Anna D. Grabowska and Dariusz Szukiewicz
Int. J. Mol. Sci. 2024, 25(14), 7527; https://doi.org/10.3390/ijms25147527 - 9 Jul 2024
Cited by 1 | Viewed by 2263
Abstract
Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) [...] Read more.
Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron–microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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17 pages, 1133 KiB  
Review
Alterations in CX3CL1 Levels and Its Role in Viral Pathogenesis
by Chunmei Zhang, Yusi Zhang, Ran Zhuang, Kun Yang, Lihua Chen, Boquan Jin, Ying Ma, Yun Zhang and Kang Tang
Int. J. Mol. Sci. 2024, 25(8), 4451; https://doi.org/10.3390/ijms25084451 - 18 Apr 2024
Cited by 4 | Viewed by 2935
Abstract
CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique [...] Read more.
CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique receptor, CX3CR1, primarily expressed in the microglia of the central nervous system (CNS). In the CNS, CX3CL1 acts as a regulator of microglia activation in response to brain disorders or inflammation. Recently, there has been a growing interest in the role of CX3CL1 in regulating cell adhesion, chemotaxis, and host immune response in viral infection. Here, we provide a comprehensive review of the changes and function of CX3CL1 in various viral infections, such as human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and cytomegalovirus (CMV) infection, to highlight the emerging roles of CX3CL1 in viral infection and associated diseases. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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17 pages, 882 KiB  
Review
Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease—Is There a Link?
by Aleksandra Stangret, Karol Artur Sadowski, Konrad Jabłoński, Janusz Kochman, Grzegorz Opolski, Marcin Grabowski and Mariusz Tomaniak
Int. J. Mol. Sci. 2024, 25(7), 3885; https://doi.org/10.3390/ijms25073885 - 30 Mar 2024
Cited by 1 | Viewed by 2356
Abstract
Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD [...] Read more.
Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition. Full article
(This article belongs to the Special Issue Fractalkine (CX3CL1) and Its Chemoattractant and Adhesion Molecule Properties in Health and Disease)
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