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.

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…Indeed, drug abusers and HIV patients with neurological symptoms had increased levels of FtH (Pitcher et al). Altogether the FtH-dependent deregulation of CXCL12/CXCR4 pathway seems to contribute to the development of cognitive dysfunction in neuroAIDS (Pitcher et al 2014). Since the CXCL12/CXCR4 signaling cascade has important roles in different cellular types and functions (Cojoc et al 2013), it could be of interest to verify the relevance of this data in cells other than neurons.…”

“…The discovery that opioids induce new synthesis of FtH can explain the heterologous desensitization observed between -opioid receptors (MOR) and CXCR4 in neurons (Sengupta et al 2009), a possible mechanism underlining the neurological dysfunction and cerebral damage determined by opiates. This activity is independent of iron binding since it is maintained by a ferroxidase deficient FtH (Pitcher et al 2014). Since CXCR4 is also a coreceptor for HIV through gp120 and TAT proteins, it is possible that ferritin H induction represents the crossroad at which the signaling cascade of opiates and HIV meet to generate the deleterious cerebral effects often observed in HIV-positive opiate-abusers (figure 7).…”

Functions of the Chemokine Receptor CXCR4 in the Central Nervous System and Its Regulation by μ-Opioid Receptors

“…CXCR4, which is the focus of this review, exerts several homeostatic effects throughout the body, including the CNS (Lazarini, Tham, Casanova, Arenzana-Seisdedos, & Dubois-Dalcq, 2003; Réaux-Le Goazigo et al, 2013). CXCL12 is the only chemokine ligand known to bind CXCR4; downstream effects of the CXCL12/CXCR4 axis in the CNS include regulation of the retinoblastoma cell-cycle protein, ensuring cell survival for postmitotic cells (Khan et al, 2008), migration of neuronal precursor cells (Stumm et al, 2003), neurogenesis (Réaux-Le Goazigo et al, 2013), protection against neurotoxic insults (Khan et al, 2004; Meucci et al, 1998; Shepherd, Loo, & Mohapatra, 2013), and regulation of dendritic spine density (Pitcher et al, 2014). These effects depend on the receptor and ligand being constitutively expressed in these tissues, which is in stark contrast to the highly inducible expression of inflammatory chemokines.…”

“…CXCR4 is expressed in the brain and the spinal cord in vitro and in vivo in a vast variety of species (Meucci et al, 1998; Ohtani et al, 1998; Pitcher et al, 2014) and in all major CNS cell types, including neurons (Meucci et al, 1998; van der Meer, Ulrich, Gonzalez-Scarano, & Lavi, 2000), astroglia (Bajetto et al, 1999), microglia (Lipfert, Odemis, Wagner, Boltze, & Engele, 2013), and oligodendrocytes (Maysami et al, 2006). The receptor has the potential to activate several distinct signaling pathways and elicit various biological responses.…”

Interactions of HIV and Drugs of Abuse

“…Interestingly, although a subset of the patients sampled undoubtedly were substance abusers, many were not—suggesting that MOR receptor is inextricably linked to processes influencing HIV pathogenesis irrespective of opiate exposure. Although the mode of action is unclear, MOR activation can alter the expression of HIV-1 chemokine coreceptors involved in HIV entry, and MOR can undergo heterologous desensitization with CXCR4 (Szabo et al, 2002; Steele, Henderson, & Rogers, 2003; Patel et al, 2006; Finley et al, 2008; Burbassi, Aloyo, Simansky, & Meucci, 2008; Pitcher et al, 2014) or CCR5 (Chen et al, 2004; Happel, Steele, Finley, Kutzler, & Rogers, 2008; Song et al, 2011). Lastly, non-opioid genes may influence opiate drug and HIV interactions.…”