Fractalkine

Fractalkine (CX3CL1) is a unique immunologic protein and member of the chemokine family that exists in both membrane-bound and secreted forms and is primarily expressed by skeletal muscle cells, vascular endothelial cells, neurons, and adipocytes PMID 37395284PMID 40943107.

• Immune Recruitment: It functions as both an adhesion molecule and a chemoattractant, playing a central role in the mobilization and recruitment of immune cells, such as monocytes, leukocytes, and natural killer (NK) cells PMID 40943107PMID 35304603.
• Metabolic Coordination: Fractalkine regulates pancreatic beta-cell function and glucose-stimulated insulin secretion, which is essential for maintaining systemic glucose tolerance PMID 40943107.
• Neurological Integrity: In the central nervous system, it is implicated in memory-associated synaptic plasticity and the maintenance of neuroprotective environments PMID 38393277PMID 40943107.
• Tissue Maintenance: It supports cellular survival across several cell lines and is involved in the processes of muscle repair and liver tissue healing PMID 40801027PMID 37395284.
• Signaling Pathways: It exerts its biological effects by binding to the CX3CR1 receptor and activating downstream signaling cascades, including c-Raf, MEK, ERK, and NF-κB PMID 38107476.

From PMID 40943107): In addition, fractalkine has been described to be modulated in response to exercise and is thus considered as an exerkine [8,150]. Lee, Y.S. et al. have demonstrated a positive effect of fractalkine on glucose stimulated insulin secretion (+58%) but preferentially mediated by an indirect mediator rather than acting as an insulin secretagogue [151]. These results are in accordance with those from Rutti et al. who have also demonstrated a protective role for the exerkine in Beta cells [152]. Fractalkine is expressed by a wide range of cell types such as endothelial cells or neurons in a physiological state and has also been described to be secreted by adipocytes [153]. Its first role was attributed to neuroprotective functions after brain injuries. As a chemokine, fractalkine is also considered an adhesion molecule in charge of cell immunity recruitment. In a pathological context, fractalkine can also be implicated in more adverse effects [154]. The chemokine is also involved in metabolic processes. Fractalkine knockout mice exhibit an impaired glucose tolerance while fractalkine administration has been reported to restore glycemia by enhancing insulin secretion [151]. It has been reported that fractalkine levels were elevated in patients with T2D compared with a control group [153,155] and is associated with inflammation [156]. Thus, once again, depending on the secretory context, secreted molecules can reveal a dual facet. Physical exercise could thus beneficially alter their functions for greater impact, notably mediated for Beta cell health improvement

Fractalkine is classified as an exerkine because its expression and circulating levels are dynamically regulated by physical activity:

• Exercise-Induced Secretion: Acute bouts of both endurance and resistance exercise significantly increase mRNA and protein expression of CX3CL1 in skeletal muscle PMID 37395284PMID 38393277.
• Circulating Response: Physical exercise elevates circulating plasma levels of fractalkine in humans, although levels typically return to baseline following chronic training PMID 35304603PMID 38393277.
• Validated Myokine: It has been identified as a plausible myokine candidate through muscle biopsy transcriptomic analysis and subsequently confirmed by ELISA PMID 39136551.

• Type 2 Diabetes (T2D) Management: Fractalkine administration has been shown to restore glycemia and improve insulin sensitivity by enhancing beta-cell function, suggesting it as a promising approach for managing metabolic dysfunction PMID 40943107.
• Neuroprotection and Stroke: It is identified as a potential therapeutic target for ischemic stroke and neurodegenerative diseases due to its ability to inhibit NLRP3 inflammasomes, reduce neuroinflammation, and promote hippocampal neurogenesis PMID 40818821PMID 38393277.
• Regenerative Capacity: By mobilizing immune cells and promoting cell migration, exercise-induced fractalkine enhances skeletal muscle regeneration and accelerates repair after injury PMID 35304603PMID 37395284.
• Cardiovascular and Hepatic Health: Fractalkine demonstrates antifibrotic effects in models of liver injury and plays a diverse role in vascular biology, including smooth muscle cell recruitment PMID 37395284.
• Osteoarthritis (OA) Biomarker: While it can contribute to cartilage destruction in pathological states, CX3CL1 serves as a valuable marker for determining OA severity and monitoring individual treatment outcomes PMID 38107476.

Fractalkine (CX3CL1) and its receptor CX3CR1 have substantial therapeutic potential across multiple disease categories, including neurodegenerative diseases, cancer, inflammatory disorders, and pain syndromes.

Neurodegenerative Diseases: The CX3CL1/CX3CR1 axis represents a promising therapeutic target for modulating neuroinflammation in conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. [1-3, PMID 34492237PMID 30496784PMID 26927660] CX3CL1 predominantly functions to reduce proinflammatory responses and exerts neuroprotective effects by regulating microglial activation. [1, 4, PMID 34492237PMID 39940727] In brain ischemia, CX3CL1 protects by modulating microglial phenotype and metabolism, inhibiting microglial activation while increasing anti-inflammatory gene expression. [5, PMID 31607865] For diabetic retinopathy specifically, fractalkine appears to mitigate inflammation, oxidative stress, and neuronal damage in early-stage disease. [6, PMID 39796231]

Cancer: The therapeutic potential in oncology is complex and context-dependent. CX3CL1 can recruit antitumor immune cells (NK cells, cytotoxic T cells) into the tumor microenvironment, and increased tumor CX3CL1 levels correlate with improved prognosis in colorectal, breast, and lung cancers. [7-8, PMID 32060841PMID 32466280] However, CX3CL1 also demonstrates protumorigenic effects in certain malignancies by promoting angiogenesis, metastasis, and interactions with tumor-associated macrophages. [9-11, PMID 39125578PMID 38731899PMID 35770395]

Inflammatory and Rheumatic Diseases: Fractalkine shows therapeutic promise in rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and scleroderma. [12, PMID 22566871] The axis also plays important roles in cardiovascular disease, atherosclerosis, glomerulonephritis, and osteoarthritis. [13-15, PMID 12969992PMID 20055718PMID 24556958]

Pain Management: The CX3CL1/CX3CR1 pathway represents a major target for treating neuropathic and spinal cord pain. [1, 14, 16, PMID 34492237PMID 20055718PMID 22530606] Despite this extensive preclinical evidence, no therapeutics targeting fractalkine or CX3CR1 have entered clinical use to date. [14, 16, PMID 20055718PMID 22530606]