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CX3CR1
CX3CR1 Full Name
chemokine (C-X3-C motif) receptor 1
CX3CR1 Introduction
CX3CR1 is a unique member of the chemokine receptor family that plays a critical role in immune regulation and cellular communication. As a typical G protein-coupled receptor (GPCR), it features a characteristic seven-transmembrane domain structure. CX3CR1 exists in two forms: a membrane-bound form that mediates direct cell adhesion via its mucin-like stalk, and a soluble form released through proteolytic cleavage, which acts as a chemoattractant guiding CX3CR1-expressing cells to specific locations. This receptor is predominantly expressed on the surface of various immune cells, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, and microglia in the central nervous system. This specific expression pattern underscores its importance in regulating the function of these cells.
The core function of the CX3CL1/CX3CR1 signaling axis is the precise regulation of cell adhesion, migration, and survival, contributing to both homeostasis and pathological responses. Binding of CX3CL1 to CX3CR1 induces conformational changes in the receptor, activating multiple downstream signaling pathways such as PLC/PKC, PI3K/Akt, MAPK, and JAK/STAT cascades. These signaling events collectively influence key cellular behaviors—including cytoskeletal reorganization for directed migration, activation of transcription factors like NF-κB to regulate inflammatory gene expression, and inhibition of apoptosis to enhance cell survival. Notably, within the central nervous system, this axis serves as a vital communication pathway between neurons and microglia: neurons express CX3CL1, while microglia express CX3CR1. This unique interaction is essential for maintaining neuronal health, regulating synaptic plasticity, and controlling neuroinflammation.
Figure 1. CX3CL1 and CX3CR1 structure, function, and signaling pathways in various pathologies, including kidney disease, cardiovascular disease, and cancer. (Source: Iwahashi Y, et al. 2025)
Owing to its central role in immune and inflammatory regulation, CX3CR1 is closely linked to the pathogenesis of various human diseases. In cardiovascular disease, particularly atherosclerosis, CX3CR1 is considered a key pro-atherogenic molecule. It promotes the adhesion of monocytes to the vascular endothelium and their migration into the subendothelial space, where they differentiate into macrophages and ultimately form foam cells—driving the formation and progression of atherosclerotic plaques. Animal studies have confirmed that CX3CR1-deficient mice exhibit significantly reduced atherosclerotic lesions. In neurodegenerative diseases, especially Alzheimer's disease (AD), the role of CX3CR1 is more complex and dual-sided. On one hand, normal CX3CR1 signaling is thought to be neuroprotective, suppressing excessive microglial activation, reducing neuroinflammation and neurotoxicity, and potentially enhancing microglial clearance of β-amyloid (Aβ). On the other hand, loss or impairment of CX3CR1 function can exacerbate disease pathology, leading to hyperphosphorylation of Tau protein, synaptic dysfunction, neuronal loss, and cognitive decline. Furthermore, this signaling axis is implicated in the pathophysiology of other conditions, including Parkinson's disease, cancer metastasis (e.g., in pancreatic and breast cancer), and rheumatoid arthritis, highlighting its broad relevance in inflammation and tumor-related diseases.
Alternate Names for CX3CR1
CX3CR1; chemokine (C-X3-C motif) receptor 1; V28; CCRL1; GPR13; CMKDR1; GPRV28; CMKBRL1; CX3C chemokine receptor 1; CMK-BRL1; CMK-BRL-1; C-X3-C CKR-1; fractalkine receptor; G protein-coupled receptor 13; G-protein coupled receptor 13; chemokine (C-X3-C) receptor 1; beta chemokine receptor-like 1; chemokine (C-C) receptor-like 1;
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