Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction
Jonathan Pitcher, … , Jay Rappaport, Olimpia Meucci
Jonathan Pitcher, … , Jay Rappaport, Olimpia Meucci
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):656-669. https://doi.org/10.1172/JCI70090.
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Research Article AIDS/HIV

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

Abstract

Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.

Authors

Jonathan Pitcher, Anna Abt, Jaclyn Myers, Rachel Han, Melissa Snyder, Alessandro Graziano, Lindsay Festa, Michele Kutzler, Fernando Garcia, Wen-Jun Gao, Tracy Fischer-Smith, Jay Rappaport, Olimpia Meucci

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Figure 3

WT FHC and mutant FHC 222 similarly inhibit CXCR4 signaling in HOS cells.

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WT FHC and mutant FHC 222 similarly inhibit CXCR4 signaling in HOS cells...
(A) WT FHC, mutant FHC 222 FHC (Mut; non–iron-binding), or EV was transfected into HOS cells (left), and the specific inability of mutant FHC 222 to bind iron was confirmed by calcein assay (right), a measure of free intracellular iron levels. Calcein fluorescence was increased by treatment with DFO or by overexpressing WT FHC, but not mutant FHC 222. (B) Effects of these proteins on CXCL12 signaling were compared by treating cells with 20 nM CXCL12 for various times. WT FHC– and mutant FHC 222–expressing cells demonstrated similar reductions in CXCL12-induced Akt and CXCR4 activation (n = 4). *P < 0.05, #P < 0.01, §P < 0.001 versus empty vector. See complete unedited blots in the supplemental material.