Potential Roles of Microglial Cell Progranulin in HIV-Associated CNS Pathologies and Neurocognitive Impairment

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.

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM 2, neurodegeneration and cognitive decline

“…We and others previously described an increase in the microglial‐derived protein sTREM2 in the CSF of both ADAD and late‐onset AD patients (Heslegrave et al , ; Piccio et al , ; Suárez‐Calvet et al , ,b). Since CSF PGRN also gradually increases during the course of the disease and it is mainly produced by activated microglia (Daniel et al , ; Naphade et al , ; Petkau et al , ; Philips et al , ; Kleinberger et al , ; Suh et al , ), we investigated whether these two proteins are associated (Figs A and B, and A–C). In a linear regression model, we found that CSF PGRN and CSF sTREM2 were significantly associated in ADAD mutation carriers of the DIAN study (β = +0.514, P < 0.0001, Fig B).…”

“…Together with the fact that CSF PGRN considerably overlaps between groups, these results show that, consistent with previous data ( CSF PGRN is associated with CSF sTREM2 and markers of neurodegeneration in both autosomal dominant and late-onset Alzheimer's disease We and others previously described an increase in the microglialderived protein sTREM2 in the CSF of both ADAD and late-onset AD patients (Heslegrave et al, 2016;Piccio et al, 2016;Suárez-Calvet et al, 2016a,b). Since CSF PGRN also gradually increases during the course of the disease and it is mainly produced by activated microglia (Daniel et al, 2000;Naphade et al, 2010;Petkau et al, 2010;Philips et al, 2010;Kleinberger et al, 2013;Suh et al, 2014), we investigated whether these two proteins are associated (Figs 6A and B, and 7A-C). In a linear regression model, we found that CSF PGRN and CSF sTREM2 were significantly associated in ADAD mutation carriers of the DIAN study (b = +0.514, P < 0.0001, Fig 6B).…”

“…Within the brain, PGRN is predominantly expressed by microglia (Zhang et al , ; Lui et al , ; Chang et al , ), but some expression is also observed in neurons. Moreover, PGRN is significantly increased upon microglial activation (Daniel et al , ; Naphade et al , ; Petkau et al , ; Philips et al , ; Kleinberger et al , ; Suh et al , ). PGRN may be involved in the modulation of neuroinflammation since PGRN‐deficient mice exhibit increased microglial activation and astrogliosis, as well as augmented expression of proinflammatory cytokines (Yin et al , , ; Ahmed et al , ; Martens et al , ; Wils et al , ; Filiano et al , ; Minami et al , ).…”

Growth Factor Signaling: Implications for Disease & Therapeutics

“…al. on the paradoxical roles of progranulin (PGRN) in modulating antiviral immunity as well as neuronal dysfunction in the context of HIV infection further emphasizes the dual roles of neuronal growth factors (Suh et al, 2013). These authors propose CSF PGRN as a candidate surrogate marker of HAND.…”

Evidence of the Innate Antiviral and Neuroprotective Properties of Progranulin

“…While neurons constitutively express PGRN, microglial cells are the primary source of regulatable PGRN in the brain [27]–[29]. Analysis of PGRN expression in systemic organs also demonstrated that tissue macrophages are the main expressors of PGRN with certain epithelial cells also expressing PGRN but at much lower levels [30]–[33]. PGRN expression in the two cell types is also differently regulated.…”