CX3CL1

CX3CL1, also known as fractalkine, is a chemokine that exists in two forms: a membrane-anchored, cell-surface protein and a soluble factor released by proteolytic shedding. It is encoded by the CX3CL1 gene and is unique among chemokines for its combination of a chemokine domain and a mucin-like stalk, which enables both adhesive and chemotactic functions. CX3CL1 binds to CX3CR1, a G protein–coupled receptor expressed on subsets of leukocytes including monocytes, natural killer cells, a fraction of T cells, and on microglia in the central nervous system.

Endothelial cells and other tissues produce CX3CL1. The membrane-bound form supports firm adhesion of CX3CR1-bearing cells to the endothelium, while metalloproteases such as ADAM10 and ADAM17 cleave CX3CL1 to generate a soluble chemokine that can act at a distance to attract CX3CR1-expressing cells.

Binding of CX3CL1 to CX3CR1 activates Gi-type G protein signaling and downstream pathways including MAP kinases and PI3K/Akt, promoting cell migration, survival, and inflammatory responses. The balance between its adhesive and chemotactic activities influences leukocyte recruitment and microglial activity, depending on the tissue context.

In physiology, the axis participates in immune surveillance, neutrophil and monocyte trafficking, and neuron–glia communication in the CNS. In pathology, it is involved in neuroinflammation, neurodegenerative disease, and vascular inflammation, including atherogenesis.

Altered CX3CL1–CX3CR1 signaling has been linked to several conditions, including Alzheimer's disease, multiple sclerosis, and other neuroinflammatory disorders, as well as cardiovascular disease and cancer microenvironments. Genetic variations in CX3CR1 can influence receptor function and disease susceptibility in some populations.

Due to its dual roles in adhesion and chemotaxis, the CX3CL1–CX3CR1 axis is under investigation as a potential therapeutic target to modulate inflammation and microglial activation. Research aims to develop antagonists or modulators that reduce chronic inflammation while preserving homeostatic immune surveillance.