CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

<jats:p>The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used<jats:italic>in vivo</jats:italic>murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and,<jats:italic>in vitro</jats:italic>, requires the activation of adenosine receptor 1 (A<jats:sub>1</jats:sub>R). We show that, in the presence of the A<jats:sub>1</jats:sub>R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in<jats:italic>A<jats:sub>1</jats:sub>R</jats:italic><jats:sup>−/−</jats:sup>mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also<jats:italic>in vivo</jats:italic>. In apparent contrast with the above reported data but in agreement with previous findings,<jats:italic>cx3cl1</jats:italic><jats:sup>−/−</jats:sup>and<jats:italic>cx3cr1<jats:sup>GFP/GFP</jats:sup></jats:italic>mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in<jats:italic>cx3cl1</jats:italic><jats:sup>−/−</jats:sup>ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and<jats:italic>cx3cl1</jats:italic><jats:sup>−/−</jats:sup>microglia<jats:italic>in vitro</jats:italic>during cotreatment with the medium conditioned by neurons damaged by oxygen-glucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosine-dependent mechanism and that the absence of constitutive CX3CL1–CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.</jats:p>