Objective: 

Glutamate (Glu) induced excitotoxicity likely is a major cause of neuronal cell death upon different brain injuries and in several pathological conditions such as AD, PD, ischemia and ALS. A role for chemokines as important molecules that mediate neuron-glia cross-talk has emerged in recent years, both in physiological and pathological conditions where they might drive brain repair and recovery. For the first time we demonstrate that in the CNS soluble CXCL16 is able to prevent neuronal cell death upon excitotoxic damage.

Methods: 

Primary hippocampal cell cultures of wt animals, CXCR6GFP/GFP, or AR3-/- mice alone or co-cultured with pure wt glia cells were used for excitotoxic experiments (Glu exposure and oxygen glucose deprivation,OGD). Specific ARs antagonists, adenosine deaminase and ELISA were used to identify mediators of CXCL16 neuroprotection.

Results: 

We found that CXCL16, acting on astrocytes, prevents hippocampal neuronal cell death upon excitotoxic damage due to excessive Glu exposure and OGD, Fig.1. CXCL16 neuroprotection requires the presence of extracellular adenosine and pharmacological or genetic inactivation of the adenosine A3 receptor (A3R) prevents CXCL16 effect, Fig.2. Moreover we found that upon stimulation with CXCL16, astrocytes release soluble factor/s, that are essential to mediate neuroprotection. In particular: i) CXCL16 induces astrocytes release of monocyte chemoattractant protein-1 MCP-1/CCL2; ii) CCL2 neutralizing antibody significantly reduces CXCL16 neuroprotection, Fig.3.

Conclusions: 

For the first time we demostrate that chemokine CXCL16 is able to mediate cross-talk between astrocytes and neighboring neurons and, in pathological conditions such as excessive Glu or OGD exposure, is able to counteract neuronal cell death through an adenosine-dependent chemokine-induced chemokine-release mechanism.