Abstract
In the CNS, the chemokine CX3CL1 (fractalkine) is expressed on neurons while its specific receptor CX3CR1 is expressed on microglia and macrophages. Microglia play an important role in health and disease through CX3CL1/CX3CR1 signaling, and in many neurodegenerative disorders, microglia dysregulation has been associated with neuro-inflammation. We have previously shown that CX3CL1 has neuroprotective effects against cerebral ischemia injury. Here, we investigated the involvement of CX3CL1 in the modulation of microglia phenotype and the underlying neuroprotective effect on ischemia injury. The expression profiles of anti- and pro-inflammatory genes showed that CX3CL1 markedly inhibited microglial activation both in vitro and in vivo after permanent middle cerebral artery occlusion (pMCAO), accompanied by an increase in the expression of anti-inflammatory genes. Moreover, CX3CL1 induces a metabolic switch in microglial cells with an increase in the expression of genes related to the oxidative pathway and a reduction in those related to the glycolytic pathway, which is the metabolic state associated to the pro-inflammatory phenotype for energy production. The data reported in this paper suggest that CX3CL1 protects against cerebral ischemia modulating the activation state of microglia and its metabolism in order to restrain inflammation and organize a neuroprotective response against the ischemic insult.
Highlights
CX3CL1 and CX3CR1 in CNSThe chemokine CX3CL1, known as fractalkine, and its receptor CX3CR1 are expressed by immune and non-immune cells throughout organisms and their expression is cell type-unique in each tissue
Since CX3CL1 is neuroprotective in ischemia (Cipriani et al, 2011) and it is known that neuro-inflammation plays a role in brain damage following ischemic insult (Iadecola and Alexander, 2001; Cheon et al, 2017), we wanted to verify the hypothesis that the neuroprotective effect of CX3CL1 was due to its ability to modulate the phenotype of microglia
Since numerous evidence suggest that upon different activation stages microglial cells switch from the oxidative phosphorylation to the anaerobic glycolysis in order to increase adenosine triphosphate (ATP) production (Voloboueva et al, 2013; Gimeno-Bayón et al, 2014) we decided to investigate whether CX3CL1 treatment could modify the metabolic repertoire of microglia
Summary
CX3CL1 and CX3CR1 in CNSThe chemokine CX3CL1, known as fractalkine, and its receptor CX3CR1 are expressed by immune and non-immune cells throughout organisms and their expression is cell type-unique in each tissue. Increasing evidence suggest a role of metabolic reprograming in the modulation of the innate inflammatory response (Orihuela et al, 2016). IL-4-stimulated BV-2 cells decreased glucose consumption and lactate production (Gimeno-Bayón et al, 2014) and primary murine microglia stimulated with IL-4/IL-13 maintained an oxidative metabolic state (Orihuela et al, 2016) suggesting that this shift was associated with a reduced need for anabolic reactions. Since neuro-inflammation caused by microglia hyperactivity has been associated with several neurodegenerative diseases (Cartier et al, 2014) and many evidence exist of a metabolic reprograming of microglia in neurodegeneration (Ulland et al, 2017), a metabolic switch toward oxidative metabolism might contribute to afford the healthful role of microglia in some pathophysiological conditions, resulting in the production of metabolites which are beneficial for neurons
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