CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Abstract

The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo 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, in vitro, requires the activation of adenosine receptor 1 (A 1 R). We show that, in the presence of the A 1 R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A 1 R ؊/؊ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1 ؊/؊ and cx3cr1 GFP/GFP mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1 ؊/؊ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1 ؊/؊ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygenglucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosinedependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…In addition, its role in modulation of cell metabolism (Cunha, 2001), neuron-glia communication (Boison et al, 2010), and the tuning of growth factor signaling (Gomes et al, 2011) is becoming evident. Indeed, we and others have recently shown that the chemokine CX 3 CL1 and the cytokines IL-6 and OSM are able to drive neuroprotection only in the presence of functional A 1 R (Biber et al, 2008;Lauro et al, 2008Lauro et al, , 2010Moidunny et al, 2010;Cipriani et al, 2011). In particular, IL-6 and OSM potentiate the expression and the function of neuronal A 1 R and therefore the ADO effects on neurotransmission and neuroprotection (Moidunny et al, 2010); on the other hand, CX 3 CL1 neuroprotection is due to ADO release from microglia, activation of A 1 R, and, possibly, the subsequent release of glial-soluble factors that contribute to neuroprotection (Lauro et al, 2010).…”

The Complexity of the Innate Immune System Activation in Stroke Pathogenesis

“…Further evidence from fractalkine studies in cerebral ischemia has shown that its exogenous administration to ischemic rats or mice is neuroprotective but, in contrast, increases brain damage in cx3cl1 −/− mice. These findings strongly indicate that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to the ischemic brain (Cipriani et al, 2011). Taking into account these findings, microglia activation state in the healthy brain may be modulated by the CXCL1-CXCR1 axis which, in turn, will determine its activation state and functionality in the context of cerebral ischemia.…”

The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury

“…The release of proinflammatory cytokines can in turn increase the neuronal damage, thus creating a vicious cycle in the course of ischemic brain injury. On the other hand, through specific chemokines and their receptors, such as CD22/CD45, CD47/ CD172a, CD200/CD200R, and CX3CL1/CX3CR1, neurons and microglia can activate a series of signaling pathways and ultimately regulate neuronal apoptosis [19][20][21].…”