A role of ferritin heavy chain in opiate-induced neuropathology

Anna Abt

doi:10.17918/00000368

In addition to the classically defined roles of chemokines as mediators of inflammatory processes, several important non-inflammatory effects of constitutive chemokine release have been described. Among these homeostatic chemokines CXCL12 and its major signaling receptor CXCR4 contribute broadly towards neuronal function and survival within the brain; CXCL12/CXCR4 signaling has been shown to promote anti-apoptotic pathways, diminish excitotoxic potential, regulate the expression of cell-cycle proteins, and contribute to progenitor cell proliferation, migration, and maturation. Previous studies have demonstrated an ability of ji-opioids including morphine to inhibit neuronal CXCR4 activation, which may contribute to neuronal dysfunction. Interestingly, this effect was shown to rely on increased levels of ferritin heavy chain (FHC), a protein typically known for its role within the iron-sequestering complex ferritin, but also recently identified as a negative regulator of CXCR4. The studies presented here aim first to examine the relationship between the iron-binding and CXCR4-regulatory functions of FHC. We demonstrate an induction of both FHC and its partner subunit ferritin light chain (FLC) in neurons in vitro and in brain tissue in vivo. The induction of FHC occurs post-transcriptionally and requires the presence of intracellular iron, suggesting the involvement of the Iron Regulatory Protein (IRP) family of translational regulators. Additionally, through the use of a mutant FHC protein unable to bind iron, we show a functional independence between the iron-binding and CXCR4-regulatory properties of FHC. A second set of studies investigates the effects of morphine, CXCL12, and FHC on neuronal function, focusing on changes in dendritic spine density. Consistent with the known neuroprotective functions of CXCL12, we demonstrate an ability of this chemokine to increase dendritic spine densities, both in vitro and in vivo. We also confirm an ability of morphine to decrease spine density, suggesting a role of FHC and decreased CXCR4 function in this process. In support of this hypothesis, we demonstrate that over-expression of FHC results in a loss of dendritic spines, and that the presence of FHC is required for morphine-induced spine loss. Together these studies demonstrate a neurophysiological outcome of morphine-induced increases in FHC, which may contribute to the neuropathology of opiate abuse.

A role of ferritin heavy chain in opiate-induced neuropathology

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A role of ferritin heavy chain in opiate-induced neuropathology

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