title: 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.forename: Jonathan
authors.initials: J
authors.lastname: Pitcher
authors.forename: Anna
authors.initials: A
authors.lastname: Abt
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Myers
authors.forename: Rachel
authors.initials: R
authors.lastname: Han
authors.forename: Melissa
authors.initials: M
authors.lastname: Snyder
authors.forename: Alessandro
authors.initials: A
authors.lastname: Graziano
authors.forename: Lindsay
authors.initials: L
authors.lastname: Festa
authors.forename: Michele
authors.initials: M
authors.lastname: Kutzler
authors.forename: Fernando
authors.initials: F
authors.lastname: Garcia
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gao
authors.forename: Tracy
authors.initials: T
authors.lastname: Fischer-Smith
authors.forename: Jay
authors.initials: J
authors.lastname: Rappaport
authors.forename: Olimpia
authors.initials: O
authors.lastname: Meucci
mesh_terms: D015526:AIDS Dementia Complex / Q000150:complications* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000818:Animals; D001052:Apoferritins / Q000737:chemistry*; D001921:Brain / Q000187:drug effects; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects; D005260:Female; D006801:Humans; D007501:Iron / Q000737:chemistry; D008251:Macaca; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000737:chemistry; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D019966:Substance-Related Disorders / Q000150:complications* / Q000503:physiopathology
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D009020:Morphine; D001052:Apoferritins; D007501:Iron