Fractalkine in the nervous system: neuroprotective or neurotoxic molecule?

Abstract

Fractalkine (CX3CL1) is an intriguing chemokine that plays a central role in the nervous system. The expression of CX3CL1 on neurons and of its receptor CX3CR1 on microglia facilitates a privileged interaction, playing important roles in regulating the function and maturation of these cells. CX3CL1 is reported to have neuroprotective and anti-inflammatory activities in several experimental systems and animal models of disease, and its expression correlates with positive outcomes in human neuropathologies. However, a comparable amount of evidence shows that CX3CL1 sustains neuroinflammatory conditions and contributes to neurotoxicity. This review discusses the evidence in favor of the CX3CL1/CX3CR1 pair being neuroprotective and other evidence that it is neurotoxic. Our aim is to stimulate future research examining the molecular and cellular determinants responsible for this unique functional switch, which could be important for several neuropathologies.

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

“…For example, it has been implicated in suppression of inflammation in the eye [24–26] and exacerbation of macrovascular disease [27,28]. Furthermore, in the CNS, CX3CR1 can exert both neuroprotective and neurotoxic effects, depending on the pathological scenario [29]. Therefore, this chemokine pathway requires tissue- and disease-specific characterization.…”

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…In addition, increased expression of certain proteins, such as fractalkine receptors, have been observed in epileptic patients [79]. (Fractalkine receptors are selectively expressed on microglia and the fractalkine chemokine is expressed by neurons, facilitating a privileged interaction between the two populations [80]). …”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…However, other evidence suggests that fractalkine sustains neuroinflammation and contributes to neurotoxicity (see [191] for a review). In any case, CX3CR1 signaling impairment has a direct influence on neurodegenerative diseases associated with neuroinflammation, microglia and/or T-cell recruitment [192,193].…”