Parkinson’s disease (PD) is characterized by the death of dopaminergic (DA) neurons in the substantia nigra and progressive loss of motor function. Histopathological analysis of PD brain tissue typically reveals intracellular protein aggregates of Synuclein-alpha, which are hypothesized to cause DA neuron apoptosis.1 In addition, extracellular neurotoxic mechanisms, mediated by increased numbers of activated glial cells and chronic central nervous system (CNS) inflammation, are thought to contribute to PD pathogenesis. However, the extent to which glial cells, specifically astrocytes, influence neuroinflammation during PD remains unclear.
Elevated cytokine concentrations are detected in postmortem samples of PD brain tissue, and evidence indicates that astrocytes are important sources of cytokines and chemokines that may modulate PD development and progression.2 For example, under pathologic conditions astrocytes upregulate the expression of proinflammatory cytokines including IL-1, IL-6, and TNF-alpha.3 In contrast, astrocytes were also reported to internalize and degrade extracellular Synuclein-alpha in mouse models of PD.4 However, the molecular mechanisms that activate astrocytes and the identity of the signaling molecules that modulate their ability to exert neuroprotection are not completely understood.
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CXCL16 Activates Astrocytes and Promotes the Secretion of Neuroprotective Factors. Brain parenchymal cells express the transmembrane chemokine CXCL16. CXCL16 is processed by a Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10) and ADAM17, and proteolytic shedding releases a soluble form of the chemokine.12 CXCL16 functions as a chemoattractant and recruits astrocytes via binding to the cognate receptor, CXCR6. The subsequent release of CCL2 from activated astrocytes requires synergistic signaling via the adenosine A3 receptor (A3R). Soluble CCL2 dampens proinflammatory signaling by macrophages.11 Via an undefined receptor, soluble CCL2 and additional factors inhibit glutamate-induced neuronal cell death.7
Astrocytes Mediate CXCL16-dependent Neuroprotection
Previous studies showed that neuron-glia crosstalk via the chemokine, CX3CL1, mediated neuroprotection against glutamate toxicity.5 Given that the related chemokine, CXCL16, is expressed by various cells in the brain and the concentration of CXCL16 is elevated in the cerebrospinal fluid of patients with a variety of neuroinflammatory disorders such as multiple sclerosis (MS), Rosito et al. hypothesized that glial cell-expressed CXCL16 contributes to neuroprotection.6,7 Western blot and immunohistochemistry experiments confirmed that CXCL16 and its receptor CXCR6 are expressed in adult mouse brain samples. Moreover, chemotaxis assays showed that astrocytes and microglia expressed functional CXCR6 and migrated in a CXCL16 concentration-dependent manner. To evaluate the neuroprotective properties of CXCL16 and potential mechanisms of neuron-glia crosstalk, the authors used hippocampal cultures containing neurons, astrocytes, and microglia. When cultures were challenged with glutamate, the number of cleaved Caspase-3+ neurons was significantly reduced in cultures pretreated with recombinant human CXCL16, suggesting that CXCL16 can exert neuroprotection.
Since previous data indicated that microglia can inhibit neuronal cell apoptosis, the authors hypothesized that microglia may mediate CXCL16-dependent neuroprotection.7,8 However, glutamate-induced neuronal cell death was not significantly inhibited when microglia were inactivated by minocycline treatment, suggesting that another cell type is responsible for transducing CXCL16-dependent neuroprotection.7 Importantly, co-culturing glutamate-challenged CXCR6+ neurons with astrocytes that were previously treated with CXCL16 significantly reduced neuronal cell death compared to culturing neurons alone. These results demonstrated that CXCL16-activated astrocytes are an important source of soluble neuroprotective factors.
To further investigate the mechanism of CXCL16-dependent neuroprotection, Rosito and colleagues evaluated the role of Adenosine Receptors (ARs), which are known to contribute to chemokine-dependent neuroprotection.9 Pharmacological AR inhibition with specific antagonists revealed that A3R was required for CXCL16-dependent neuroprotection.7 Moreover, treating astrocytes with an A3R agonist stimulated the release of Chemokine Ligand 2 (CCL2), which is consistent with previous results showing that A3R receptor signaling induces CCL2 expression.7,9 To determine whether CCL2 mediates CXCL16 neuroprotection in this context, hippocampal cultures were treated with anti-CCL2 antibodies in the presence of glutamate toxicity and CXCL16. An increase in CXCL16-induced neuronal cell survival was blocked by anti-CCL2 antibodies, indicating that CCL2, likely derived from astrocytes, can protect neurons from glutamate-induced apoptosis.7
Glia-mediated neurotoxicity and neuroprotection are also important mechanisms in the pathogenesis of other neurodegenerative conditions including AIDS dementia complex. AIDS dementia complex is characterized by cognitive decline, myelopathy, and motor dysfunction.10 A recent report showed that SIV-infected astrocytes secrete high levels of CCL2, and macrophages in the CNS respond by downregulating expression of the proinflammatory and neurotoxic cytokines, IFN-alpha and TNF-Related Apoptosis-inducing Ligand (TRAIL).11
Collectively, these studies provide additional evidence that chemokine-mediated crosstalk between neurons and glia represents an important neuroprotective mechanism. Notably, astrocyte-secreted CCL2, a proinflammatory chemokine known to promote monocyte and lymphocyte recruitment, was shown to exert neuroprotective capabilities in glutamate toxicity models.7,11 Harnessing the neuroprotective effects of CXCL16-induced astrocyte release of CCL2 in the brain could have implications for combating glutamate-induced cell death in neurodegenerative diseases including PD, multiple sclerosis, and Alzheimer’s disease.
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