Expression of fractalkine and its receptor, CX₃CR1, in response to ischaemia‐reperfusion brain injury in the rat

Abstract

Fractalkine is a neuronally expressed chemokine that acts through its G-protein-coupled receptor CX3CR1, localized on microglial and immune cells. Fractalkine might be involved in neuroinflammatory processes secondary to neuronal damage, which normally occur in a time frame of days after ischaemia. We evaluated by in situ hybridization and immunohistochemistry the expression of fractalkine and CX3CR1 in the rat brain, after a transient occlusion of the middle cerebral artery. We found that at 12 h after ischaemia neuronal fractalkine expression was transiently increased in scattered necrotic neurons of the cortex and lost from the ischaemic striatum. At 24 and 48 h after ischaemia, fractalkine immunoreactivity was strongly increased in morphologically intact cortical neurons of the ischaemic penumbra where also the stress-inducible HSP-72 was strongly up-regulated. The intensity of fractalkine immunoreactivity of neurons in the penumbra returned to basal levels at 7 days after ischaemia. Fractalkine synthesis was also induced in endothelial cells of the infarcted area, at 48 h and 7 days after ischaemia. CX3CR1 expression was detected in the activated microglial cells of the ischaemic tissue 24 and 48 h after ischaemia, and became strongly up-regulated in macrophages/phagocytic microglia inside the infarcted tissue 7 days after ischaemia. These data suggest that fractalkine may participate in the activation and chemoattraction of microglia into the infarcted tissue, and contribute to the control of leucocyte trafficking from blood vessels into the injured area.

Pathobiology of cervical spondylotic myelopathy

“…In the central nervous system (CNS), neurons express fractalkine (CX3CL1) on their membranes, while its receptor (CX3CR1) is highly expressed on microglia [38]. Based on evidence from other CNS disorders, we may expect that CX3CR1/L1 interactions are an important component of neuroinflammation; however, the role is disease specific [39][40][41]. Importantly, it has been demonstrated that ischemia leads to CX3CR1/L1-mediated microglia activation [42] which potentially establishes the CX3CR1/L1 pathway as a critical mechanistic link between chronic hypoxia and neuroinflammation in CSM.…”

Microglial Activation in Stroke: Therapeutic Targets

“…Following ischemia, its expression has been localized to viable neurons in the infarct periphery as well as some endothelial cells. 91 Fractalkine is constitutively expressed in the CNS, mainly by neurons, and is upregulated and released in response to proinflammatory stimuli. 92 Expression of the fractalkine receptor, CX3CR1, is observed only on microglia and macrophages, suggesting that fractalkine is involved in neuron-microglial signaling.…”

“…92 Expression of the fractalkine receptor, CX3CR1, is observed only on microglia and macrophages, suggesting that fractalkine is involved in neuron-microglial signaling. 91 Mice deficient in fractalkine 93 or its microglial receptor 94 have smaller infarct sizes and better functional outcomes. CX3CR1 antagonists are currently under development.…”

The Chemokine CX3CL1 Reduces Migration and Increases Adhesion of Neurons with Mechanisms Dependent on the β1 Integrin Subunit

“…CX3CL1 is present on cells as a transmembrane molecule, which is transformed into the soluble form upon extracellular shedding, mediated by the activation of the constitutive or inducible metalloproteinases ADAM10 and ADAM17 (12)(13)(14). Several pieces of evidence describe that toxic insults and nerve injuries induce an increase of CX3CL1 expression and its release from neurons with microglial recruitment (2,11,13,(15)(16)(17). The cytokine milieu locally generated in different chronic and acute neuroinflammatory conditions may influence glial expression of CX3CL1 and CX3CR1 (10).…”