Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia

Rachel Williams, Honghong Yao, Fuwang Peng, Yanjing Yang, Crystal Bethel-Brown, Shilpa J Buch

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

With the increasing prevalence of HIV-associated neurocognititve disorders (HAND), understanding the mechanisms by which HIV-1 induces neuro-inflammation and subsequent neuronal damage is important. The hallmark features of HIV-encephalitis, the pathological correlate of HIV-associated Dementia (HAD), are gliosis, oxidative stress, chemokine dysregulation, and neuronal damage/death. Since neurons are not infected by HIV-1, the current thinking is that these cells are damaged indirectly by pro-inflammatory chemokines released by activated glial cells. CXCL10 is a neurotoxic chemokine that is upregulated in astroglia activated by HIV-1 Tat, IFN-γ, and TNF-α. In this study we have demonstrated that HIV-1 Tat increases CXCL10 expression in IFN-γ and TNF-α stimulated human astrocytes via NADPH oxidase. We have shown that the treatment of astrocytes with a mixture of Tat and cytokines leads to a respiratory burst that is abrogated by apocynin, an NADPH oxidase inhibitor. Pretreatment of Tat, IFN-γ, and TNF-α stimulated astrocytes with apocynin also resulted in concomitant inhibition of CXCL10 expression. Additionally, apocynin was also able to reduce Tat and cytokine-mediated activation of the corresponding signaling molecules Erk1/2, Jnk, and Akt with a decrease in activation and nuclear translocation of NF-κB, important regulators of CXCL10 induction. Understanding the mechanisms involved in reducing both oxidative stress and the release of pro-inflammatory agents could lead to the development of therapeutics aimed at decreasing neuro-inflammation in patients suffering from HAD.

Original languageEnglish (US)
Pages (from-to)611-621
Number of pages11
JournalGlia
Volume58
Issue number5
DOIs
Publication statusPublished - Apr 1 2010

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Keywords

  • Astrocytes
  • CXCL10
  • HIV-associated dementia
  • NADPH oxidase

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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