CX3C chemokine ligand 1 (CX3CL1), also known as fractalkine (FKN), is a chemokine belonging to the CX3C family. CX3CL1 is secreted by neurons and plays an important role in modulating glial activation in the central nervous system after binding to its sole receptor CX3CR1 which mainly is expressed on microglia. The CX3CL1/CX3CR1 interaction is an important bridge connecting neuron and microglia¹.

CX3CL1 is a large cytokine protein with an extended mucin-like stalk and a chemokine domain at the N-terminus. It is the only member of CX3C family which belongs to the large family of small secreted chemotactic cytokines. CX3CL1 is highly and constitutively expressed in hippocampal and cortical neurons. It exists in both secreted and membrane-bound form. While the secreted form contains only the chemokine domain located in the N-terminus, the membrane-bound form contains the chemokine domain, a mucin-like stalk, a transmembrane domain and an intracellular C-terminal domain. The membrane-tethered mucin stalk acts as a cell adhesion molecule adhering to microglia during an inflammatory reaction, it can be cleaved to produce a soluble glycoprotein by metalloproteinases ADAM 10 and ADAM 17 or lysosomal cysteine protease and cathepsin S (CatS), The soluble form has been proposed to act as a chemoattractant and can serve as a signaling molecule mediating neural/microglial interactions via its receptor CX3CR1, mainly expressed on microglia and partly on astrocyte as well as on neurons in the CNS. The CX3CL1/CX3CR1 interaction on microglia is likely to alter the microglial state to a more neuroprotective one.  Notably, transmembrane and soluble CX3CL1 elicit different cytokine responses in immune cells^1-3.

CX3CL1 has been associated with learning and memory as CX3CL1 is upregulated in the rat hippocampus during memory-associated synaptic plasticity. It is considered as a potent neuromodulator of the evoked excitatory synaptic transmission and plays a major role in synaptic plasticity and neuroprotection^1,4.