Disruption of neuronal CXCR4 function by opioids: Preliminary evidence of Ferritin Heavy Chain as a potential etiological agent in neuroAIDS

Abstract

The chemokine CXCL12 and its receptor, CXCR4, regulate neuronal migration, differentiation, and survival. Alterations of CXCL12/CXCR4 signaling are implicated in different neuropathologies, including the neurological complications of HIV infection. Opiates are important co-factors for progression to neuroAIDS and can disrupt the CXCL12/CXCR4 axis in vitro and in vivo. This paper will review recently identified mechanisms of opiate-induced CXCR4 impairment in neurons and introduce results from pilot studies in human brain tissue, which highlight the role of the protein ferritin heavy chain in HIV neuropathology in patients with history of drug abuse. KeywordsCXCR4; CXCL12; opiates; ferritin heavy chain; neuroAIDS; NR2B 1: IntroductionHuman immunodeficiency virus (HIV) continues to profoundly impact public health within the United States and around the world. With over 50,000 new cases of HIV-1 infection reported annually in the United States alone, the prevalence of individuals diagnosed with HIV/AIDS is increasing steadily according to the most recent reports from the Centers for Disease Control and Prevention (CDC, 2009). The social impact of HIV/AIDS disproportionally affects males and overwhelmingly affects minorities, underscoring disparities in risk factors and public health access across the socioeconomic spectrum (CDC, 2009). One such risk factor, illicit opiate abuse through intravenous drug use (IVDU), increases the risk of HIV exposure but also accelerates disease progression and exacerbates neurological involvement (Hu et al., 2005, Khurdayan et al., 2004, Hauser et al., 2006. Given the success of combined antiretroviral therapy (cART) and efforts to broaden treatment to include medically underserved areas, the average life expectancy of HIV Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Harrison et al., 2010), revealing the neurological impact of chronic HIV infection on an aging population (Valcour et al., 2004) and highlighting the importance of identifying the molecular mechanisms essential to the ability of opiates to promote neurological dysfunction. NIH Public Access 2: HIV neuropathology and Drug abuseThe natural history of HIV infection, coupled with the typically poor central nervous system (CNS) penetration of cART, predispose individuals for CNS complications over time.Following an acute, systemic viremia HIV seeds numerous tissues in the body, including the CNS, allowing it to harbor itself in an immunologically privileged environment and replicate chronically (Ghafouri et al., 2006). The resulting infection within the CNS can remain as...

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

“…As revealed by immunohistochemistry and multispectral image analysis (41), in which the OD of FHC was quantified specifically within cells staining positive for the neuronal marker MAP2 (Supplemental Figure 1), basal expression of FHC protein within human cortical neurons was normally low; within the control samples, the absolute OD of the FHC/chromogen complex was mainly distributed just above the level of detection ( Figure 1A). In individuals with a history of drug use, mean FHC expression was significantly increased and also showed increased variability.…”

CXCL12-CXCR4 Promotes Proliferation and Invasion of Pancreatic Cancer Cells

“…However, more recently, this axis has been found to not only contribute to immunoregulation and mediatiation of the normal inflammatory response, but also play an important role in human immunological diseases, especially in mediating HIV infection (Pitcher et al, 2010;Patrussi and Baldari, 2011). Increasingly, studies have been devoted to uncovering the effects of CXCL12-CXCR4 on behavior of tumor cells, especially on proliferation, differentiation, directional migration, infiltration, and invasion of malignant cells (Horuk, 2001;Dömötör et al, 2005).…”

Regulation of Neuronal Ferritin Heavy Chain, A New Player in Opiate-Induced Chemokine Dysfunction

“…A relevance of these findings for human disease is supported by preliminary studies in post mortem human brain tissue, showing an elevation in numbers of FHC-positive cells in the frontal cortex of opiate drug abusers (Pitcher et al, 2010). An increase in cortical FHC was also observed in patients with HIV-associated dementia (Pitcher et al, 2010), a neurodegenerative complication of HIV with increased prevalence and rate of progression among opiate users (Davies et al, 1998; Bell et al, 2006; Hauser et al, 2006; Nath, 2010).…”

“…An increase in cortical FHC was also observed in patients with HIV-associated dementia (Pitcher et al, 2010), a neurodegenerative complication of HIV with increased prevalence and rate of progression among opiate users (Davies et al, 1998; Bell et al, 2006; Hauser et al, 2006; Nath, 2010). Importantly, this disease-associated elevation of FHC coincided with a decrease in phosphorylated (active) CXCR4, supporting a role of FHC-induced CXCR4 inhibition in pathological neuronal dysfunction (Pitcher et al, 2010). …”