TY - JOUR
T1 - Potential roles of microglial cell progranulin in HIV-associated CNS pathologies and neurocognitive impairment
AU - Suh, Hyeon Sook
AU - Gelman, Benjamin B.
AU - Lee, Sunhee C.
N1 - Funding Information:
Acknowledgments The authors thank the National NeuroAIDS Tissue Consortium (NNTC) for providing brain tissue and brain gene array data. We thank the CHARTER Group for providing clinical samples of blood plasma and cerebrospinal fluid. We also thank Dr Namjong Choi for excellent immunohistochemistry. We are grateful to Drs Scott Letendre, Yungtai Lo, Susan Morgello, and Yousin Suh for many helpful discussions. This study was supported by the NIH grants RO1MH55477, KO1MH084705 and the Einstein CFAR grant (P30AI051519). The NNTC is supported by the NIH including U01 MH083507, U01 MH083506, U01 MH083501, U01 MH083500, and U01 MH083545. The CHARTER study was supported by N01 MH22005, HHSN271201000036C and HHSN271201000030C from the National Institutes of Health.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Cytokines
KW - Growth factor
KW - HIV encephalitis (HIVE)
KW - HIV-associated neurocognitive disorder (HAND)
KW - Human
KW - Innate immunity
KW - Microglia
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U2 - 10.1007/s11481-013-9495-z
DO - 10.1007/s11481-013-9495-z
M3 - Review article
C2 - 23959579
AN - SCOPUS:84896548321
SN - 1557-1890
VL - 9
SP - 117
EP - 132
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 2
ER -