CX3CL1, also known as Fractalkine or Neurotactin, is a unique chemokine in the CX3C chemokine family. Initially translated as a transmembrane protein, it can be proteolytically processed into a soluble form. CX3CL1 signals through its sole receptor CX3CR1, predominantly expressed on microglial cells in the central nervous system (CNS). It plays a crucial role in modulating neuroinflammation, with functions in reducing pro-inflammatory responses and often showing neuroprotective effects. It is also involved in processes like cell adhesion, chemotaxis, and the host immune response [1,5].

In neurodegenerative diseases, studies on the CX3CL1/CX3CR1 signaling axis have been extensive. In Alzheimer's disease, CX3CL1 impacts Aβ clearance, tau phosphorylation, microglia activation, and priming, suggesting its biochemical pathway could be a target for treatment strategies [4]. In Parkinson's, Huntington's, and other neurodegenerative diseases, the CX3CL1/CX3CR1 signaling shows complex roles, sometimes neuroprotective and in some cases promoting neurodegeneration [1,6]. In peritoneal fibrosis, the interaction between CX3CL1 expressed on peritoneal mesothelial cells and CX3CR1 on macrophages promotes fibrosis, indicating it could be a therapeutic target [2]. In cancer, CX3CL1 is involved in anticancer functions of lymphocytes, yet has variable prognostic associations depending on cancer types [3].

In conclusion, CX3CL1 is a multifunctional chemokine with a significant impact on various biological processes and disease conditions. Studies, including those using gene-knockout (KO) or conditional-knockout (CKO) mouse models (implied by research on the signaling axis), have revealed its complex roles in neurodegenerative diseases, peritoneal fibrosis, and cancer. Understanding CX3CL1 is crucial for developing potential therapeutic strategies for these diseases.

References:

1. Subbarayan, Meena S, Joly-Amado, Aurelie, Bickford, Paula C, Nash, Kevin R. 2021. CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases. In Pharmacology & therapeutics, 231, 107989. doi:10.1016/j.pharmthera.2021.107989. https://pubmed.ncbi.nlm.nih.gov/34492237/

2. Helmke, Alexandra, Nordlohne, Johannes, Balzer, Michael S, Haller, Hermann, von Vietinghoff, Sibylle. 2019. CX3CL1-CX3CR1 interaction mediates macrophage-mesothelial cross talk and promotes peritoneal fibrosis. In Kidney international, 95, 1405-1417. doi:10.1016/j.kint.2018.12.030. https://pubmed.ncbi.nlm.nih.gov/30948201/

3. Korbecki, Jan, Simińska, Donata, Kojder, Klaudyna, Chlubek, Dariusz, Baranowska-Bosiacka, Irena. 2020. Fractalkine/CX3CL1 in Neoplastic Processes. In International journal of molecular sciences, 21, . doi:10.3390/ijms21103723. https://pubmed.ncbi.nlm.nih.gov/32466280/

4. Bivona, Giulia, Iemmolo, Matilda, Ghersi, Giulio. 2023. CX3CL1 Pathway as a Molecular Target for Treatment Strategies in Alzheimer's Disease. In International journal of molecular sciences, 24, . doi:10.3390/ijms24098230. https://pubmed.ncbi.nlm.nih.gov/37175935/

5. Zhang, Chunmei, Zhang, Yusi, Zhuang, Ran, Zhang, Yun, Tang, Kang. 2024. Alterations in CX3CL1 Levels and Its Role in Viral Pathogenesis. In International journal of molecular sciences, 25, . doi:10.3390/ijms25084451. https://pubmed.ncbi.nlm.nih.gov/38674036/

6. Iemmolo, Matilda, Ghersi, Giulio, Bivona, Giulia. 2023. The Cytokine CX3CL1 and ADAMs/MMPs in Concerted Cross-Talk Influencing Neurodegenerative Diseases. In International journal of molecular sciences, 24, . doi:10.3390/ijms24098026. https://pubmed.ncbi.nlm.nih.gov/37175729/