Potential roles of microglial cell progranulin in HIV-associated CNS pathologies and neurocognitive impairment

Hyeon Sook Suh, Benjamin B. Gelman, Sunhee C. Lee

Research output: Contribution to journalReview article

6 Scopus citations

Abstract

Progranulin (PGRN) is a highly unusual molecule with both neuronal and microglial expression with two seemingly unrelated functions, i.e., as a neuronal growth factor and a modulator of neuroinflammation. Haploinsufficiency due to loss of function mutations lead to a fatal presenile dementing illness (frontotemporal lobar degeneration), indicating that adequate expression of PGRN is essential for successful aging. PGRN might be a particularly relevant factor in the pathogenesis of HIV encephalitis (HIVE) and HIV-associated neurocognitive disorders (HAND). We present emerging data and a review of the literature which show that cells of myeloid lineage such as macrophages and microglia are the primary sources of PGRN and that PGRN expression contributes to pathogenesis of CNS diseases. We also present evidence that PGRN is a macrophage antiviral cytokine. For example, PGRN mRNA and protein expression are significantly upregulated in brain specimens with HIVE, and in HIV-infected microglia in vitro. Paradoxically, our preliminary CHARTER data analyses indicate that lower PGRN levels in CSF trended towards an association with HAND, particularly in those without detectable virus. Based upon these findings, we introduce the hypothesis that PGRN plays dual roles in modulating antiviral immunity and neuronal dysfunction in the context of HIV infection. In the presence of active viral replication, PGRN expression is increased functioning as an anti-viral factor as well as a neuroprotectant. In the absence of active HIV replication, ongoing inflammation or other stressors suppress PGRN production from macrophages/microglia contributing to neurocognitive dysfunction. We propose CSF PGRN as a candidate surrogate marker for HAND.

Original languageEnglish (US)
Pages (from-to)117-132
Number of pages16
JournalJournal of Neuroimmune Pharmacology
Volume9
Issue number2
DOIs
StatePublished - Mar 2014

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Keywords

  • Cytokines
  • Growth factor
  • HIV encephalitis (HIVE)
  • HIV-associated neurocognitive disorder (HAND)
  • Human
  • Innate immunity
  • Microglia

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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