CX3CR1, the C-X3-C motif chemokine receptor 1, functions as the sole receptor for the chemokine CX3CL1. It is expressed on various immune cells like microglial cells in the central nervous system (CNS), macrophages, monocytes, and CD8+ T cells [1,2,4]. Signaling via CX3CR1 upon interaction with CX3CL1 regulates multiple biological functions, playing a crucial role in neuron-glial signaling, immune response, and inflammation-related processes [1].

In a murine peritoneal dialysis (PD) model, CX3CR1, mostly expressed on macrophages in the peritoneal wall, promoted fibrosis induced by chronic dialysate exposure. This suggests that macrophage-mesothelial cell crosstalk through CX3CR1-CX3CL1 interaction enhances mesothelial TGFβ production, promoting peritoneal fibrosis [2]. In a germinal matrix hemorrhage (GMH) rat model, administration of CX3CR1 CRISPR or a CX3CR1 inhibitor abolished the protective effect of recombinant fractalkine (r-FKN), which otherwise promoted hematoma resolution, attenuated neuroinflammation, and improved neurological deficits through the AMPK/PPARγ signaling pathway [3]. Also, in familial tauopathy, single-cell RNA-seq of human peripheral blood mononuclear cells showed a marked reduction in the expression of CX3CR1 in monocytes and NK cells, suggesting modulation of peripheral immune cell expression by tau-associated pathophysiologic changes [5].

In conclusion, CX3CR1 is essential in regulating immune and inflammatory responses. Studies using gene-knockout or inhibitor-based models in various disease conditions such as peritoneal fibrosis, GMH, and tauopathy have revealed its role in promoting fibrosis, mediating hematoma resolution, and being affected by tau-related pathophysiology respectively. Understanding CX3CR1's function provides insights into disease mechanisms and potential therapeutic targets 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. Chen, Xionghui, He, Xuying, Xu, Feng, Zhou, Youxin, Tang, Jiping. 2023. Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH. In Stroke, 54, 2420-2433. doi:10.1161/STROKEAHA.123.043005. https://pubmed.ncbi.nlm.nih.gov/37465997/

4. Ma, Jiajin, Wu, Yue, Wu, Shaoxian, Jiang, Jingting, Zheng, Xiao. 2024. CX3CR1+CD8+ T cells: Key players in antitumor immunity. In Cancer science, 115, 3838-3845. doi:10.1111/cas.16359. https://pubmed.ncbi.nlm.nih.gov/39377122/

5. Sirkis, Daniel W, Warly Solsberg, Caroline, Johnson, Taylor P, Geier, Ethan G, Yokoyama, Jennifer S. 2023. Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy. In Genome medicine, 15, 53. doi:10.1186/s13073-023-01205-3. https://pubmed.ncbi.nlm.nih.gov/37464408/