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Review
. 2017 Apr;54(3):2167-2188.
doi: 10.1007/s12035-016-9787-4. Epub 2016 Mar 1.

Analysis of the Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Traumatic Brain and Spinal Cord Injury: Insight into Recent Advances in Actions of Neurochemokine Agents

Łukasz A Poniatowski  1 , Piotr Wojdasiewicz  2   3   4 , Maciej Krawczyk  5   6 , Dariusz Szukiewicz  2 , Robert Gasik  3   4 , Łukasz Kubaszewski  4   7 , Iwona Kurkowska-Jastrzębska  5
Affiliations
Review

Analysis of the Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Traumatic Brain and Spinal Cord Injury: Insight into Recent Advances in Actions of Neurochemokine Agents

Łukasz A Poniatowski et al. Mol Neurobiol. 2017 Apr.

Abstract

CX3CL1 (fractalkine) is the only member of the CX3C (delta) subfamily of chemokines which is unique and combines the properties of both chemoattractant and adhesion molecules. The two-form ligand can exist either in a soluble form, like all other chemokines, and as a membrane-anchored molecule. CX3CL1 discloses its biological properties through interaction with one dedicated CX3CR1 receptor which belongs to a family of G protein-coupled receptors (GPCR). The CX3CL1/CX3CR1 axis acts in many physiological phenomena including those occurring in the central nervous system (CNS), by regulating the interactions between neurons, microglia, and immune cells. Apart from the role under physiological conditions, the CX3CL1/CX3CR1 axis was implied to have a role in different neuropathologies such as traumatic brain injury (TBI) and spinal cord injury (SCI). CNS injuries represent a serious public health problem, despite improvements in therapeutic management. To date, no effective treatment has been determined, so they constitute a leading cause of death and severe disability. The course of TBI and SCI has two consecutive poorly demarcated phases: the initial, primary injury and secondary injury. Recent evidence has implicated the role of the CX3CL1/CX3CR1 axis in neuroinflammatory processes occurring after CNS injuries. The importance of the CX3CL1/CX3CR1 axis in the pathophysiology of TBI and SCI in the context of systemic and direct local immune response is still under investigation. This paper, based on a review of the literature, updates and summarizes the current knowledge about CX3CL1/CX3CR1 axis involvement in TBI and SCI pathogenesis, indicating possible molecular and cellular mechanisms with a potential target for therapeutic intervention.

Keywords: CX3CL1; CX3CR1; Chemokines; Fractalkine; Neuroinflammation; Spinal cord injury; Traumatic brain injury.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The schematic structure of two-form chemokine ligand CX3CL1 (fractalkine). a Membrane-anchored form of CX3CL1 showing specific regions of the molecule and the site of the cleaving action of the metalloproteinase ADAM10 and ADAM17 (TACE). b The soluble form of CX3CL1 (sCX3CL1), produced by metalloproteinase cleaving. The N-terminal chemokine domain (CD) containing the CX3C motif is shown in greater detail including important parts of the secondary and tertiary protein structure. Adopted and modified with permission from Wojdasiewicz P, Poniatowski ŁA et al. (2014) The Chemokine CX3CL1 (Fractalkine) and its Receptor CX3CR1: Occurrence and Potential Role in Osteoarthritis. Arch Immunol Ther Exp (Warsz) 62(5):395-403. doi: 10.1007/s00005-014-0275-0
Fig. 2
Fig. 2
The schematic structure of CX3CR1 chemokine receptor. The molecular structure of the receptor includes seven α-helical transmembrane domains (TM1–TM7), three extracellular (EL1, EL2, EL3) and three intracellular loops (IL1, IL2, IL3), an extracellular N-terminus, and an intracellular C-terminus. The disulphide bond is shown between two highly conserved cysteines (Cys) which are located respectively at the top of the third transmembrane domain (TM3) and the second extracellular loop (EL2). The second intracellular loop (IL2) contains a conserved seven amino acid sequence Asp-Arg-Tyr-Leu-Ala-Ile-Val (DRYLAIV motif) which serves as Gαi heterotrimeric protein docking site. a CX3CR1 receptor shown from the side perspective. b CX3CR1 receptor shown from the intracellular perspective
Fig. 3
Fig. 3
The schematic representation of the physiological and pathological role of CX3CL1/CX3CR1 axis in the context of bidirectional cross talk between neurons and microglia. a Under physiological conditions, microglia undergo tonic signaling through the CX3CL1/CX3CR1 axis, which facilitates the maintenance of its cells in a quiescent state. b Under pathological conditions, the homeostasis cross talk between neurons and microglia through the CX3CL1/CX3CR1 axis is disrupted. Upregulated levels of several cytokines, chemokines, and other mediators create a specific inflammatory environment, which results in paradoxical promotion through the CX3CL1/CX3CR1 axis, activation and proliferation of microglia, and the infiltration of peripheral immune cells
Fig. 4
Fig. 4
Overview and summary of potential CX3CL1/CX3CR1 axis-associated therapeutic options for management of traumatic brain and spinal cord injury. GC glucocorticoids, MSC mesenchymal stem cells; (+) refer to activation and (−) to inhibition of CX3CL1/CX3CR1 axis by acting on protein expression and CX3CL1/CX3CR1 interaction
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