Trasmembrane chemokines CX3CL1 and CXCL16 drive interplay between neurons, microglia and astrocytes to counteract pMCAO and excitotoxic neuronal death

Abstract

Upon noxious insults, cells of the brain parenchyma activate endogenous self-protective mechanisms to counteract brain damage. Interplay between microglia and astrocytes can be determinant to build a physiological response to noxious stimuli arisen from injury or stress, thus understanding the cross talk between microglia and astrocytes would be helpful to elucidate the role of glial cells in endogenous protective mechanisms and might contribute to the development of new strategy to mobilize such program and reduce brain cell death. Here we demonstrate that chemokines CX3CL1 and CXCL16 are molecular players that synergistically drive cross-talk between neurons, microglia and astrocytes to promote physiological neuroprotective mechanisms that counteract neuronal cell death due to ischemic and excitotoxic insults. In an in vivo model of permanent middle cerebral artery occlusion (pMCAO) we found that exogenous administration of soluble CXCL16 reduces ischemic volume and that, upon pMCAO, endogenous CXCL16 signaling restrains brain damage, being ischemic volume reduced in mice that lack CXCL16 receptor. We demonstrated that CX3CL1, acting on microglia, elicits CXCL16 release from glia and this is important to induce neroprotection since lack of CXCL16 signaling impairs CX3CL1 neuroprotection against both in vitro Glu-excitotoxic insult and pMCAO. Moreover the activity of adenosine receptor A3R and the astrocytic release of CCL2 play also a role in trasmembrane chemokine neuroprotective effect, since their inactivation reduces CX3CL1- and CXCL16 induced neuroprotection.

The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects

“…These reports identified CX3CL1/CX3CR1 signaling as an actor in stroke pathophysiology, especially through activation of microglia, astrocytes, or macrophages toward a proinflammatory detrimental state. On the other hand, other studies have shown neuroprotective effects of this signaling in cerebral ischemia in that a strong positive correlation was found between high plasmatic concentration of CX3CL1 and better clinical outcome in stroke patients . Interestingly, Rosito et al .…”

Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke

“…However, other studies highlighted beneficial effects correlating high plasmatic concentrations of CX3CL1 and good clinical outcomes [70,72]. Interestingly, Rosito and co-workers proposed that the release of chemokines, such as CX3CL1, CXCL16, and CCL2 affects neurons, microglia, and astrocytes during brain ischemia [73]. These molecules might be considered as endogenous self-protective compounds limiting the cell damage in the ischemic penumbra [73].…”

Fractalkine in the nervous system: neuroprotective or neurotoxic molecule?

“…Stimulation of microglia with CX3CL1 induces an increase in extracellular adenosine, most likely derived from ATP, whose action on specific receptors counteracts the excitotoxic cell damage triggered by the activation of different glutamate (Glu) receptors. Specifically, activation of the adenosine receptors A 1 R and A 3 R modulates CX3CL1 neuroprotection against Glu excitoxicity, while A 2A R is involved in neuroprotection against N ‐methyl‐ d ‐aspartate receptor (NMDAR) overactivation . CX3CL1 neuroprotection against Glu challenge requires the activity of A 1 R expressed on astrocytes, which is necessary for increased expression and upregulation of the excitatory amino acid transporter GLT‐1 and thereby leads to a more efficient removal of glutamate from the synaptic cleft .…”

“…Moreover, CX3CL1 acts synergistically with other chemokines to promote neuroprotection. Recent data have shown that CX3CL1 elicits from glia the release of CXCL16 that, in turn, contributes to neuronal survival via a mechanism that involves the activation of astrocytic A 3 R and the release of CCL2 . CX3CL1 also induces the release of d ‐serine from glia, via an A 2A R‐mediated mechanism, that, besides modulating the NMDAR response, contributes to the neuroprotective effect by mediating the phosphorylation of cyclic AMP response element–binding protein (CREB) .…”