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Updated: Apr 14, 2026
Isolation, Transfection, and Culture of Primary Human Monocytes
Published on: December 16, 2019
Role for cFMS in maintaining alternative macrophage polarization in SIV infection: implications for HIV
Lindsey Gerngross1, Gabrielle Lehmicke2, Aghilas Belkadi3
1Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, MERB, Room 748, Philadelphia, PA, 19140, USA. lindsey.gerngross@temple.edu.
Background:
Macrophage-colony stimulating factor (M-CSF) has been implicated in HIV neuropathogenesis through its ability to modulate activation of macrophages (MΦs) and microglia, as well as enhance the susceptibility of these cells to infection and promote virus production. We have recently reported that MΦs accumulating perivascularly and within nodular lesions in archival brain tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques with encephalitis (SIVE) express M-CSF. In contrast, IL-34, which shares the same receptor, cFMS, was observed more often in parenchymal cells.
Methods:
Frontal white and grey matter from non-infected and SIV-infected rhesus macaques with and without SIVE were examined by single- and double-label immunohistochemistry for M-CSF, IL-34, and CD163 expression. Primary rhesus macaque and human peripheral blood mononuclear cells were cultured with and without 2.5 ng/ml M-CSF or IL-34 alone and with 470 nM or 4.7 μM of GW2580, a receptor tyrosine kinase inhibitor with high specificity for cFMS. After 24 h, cells were analyzed by flow cytometry to examine the effect of these cytokines on promoting an M2 monocyte/MΦ phenotype.
Results:
Here, we demonstrate that in SIVE brain, accumulating M-CSF(+) MΦs are also CD163(+), while IL-34 does not appear to co-localize significantly with CD163 in the parenchyma. We further demonstrate that M-CSF and IL-34 are expressed by neurons in normal brain but are altered in SIV and SIVE. Through in vitro studies, we show that M-CSF and IL-34 upregulate CD163, a marker for type 2 activation of MΦs (M2), by primary monocytes, which is attenuated by the addition of GW2580.
Conclusions:
Together, these data suggest that both cFMS ligands may promote and/or prolong M2 activation of MΦs and microglia in brains of SIV-infected animals with encephalitis. As such, cFMS signaling may be an attractive target for eliminating long-lived MΦ reservoirs of HIV infection in brain, as well as other tissues.
Insights
Macrophage-colony stimulating factor (M-CSF) and IL-34 promote M2 macrophage activation in SIV encephalitis. Targeting cFMS signaling may help eliminate HIV reservoirs in the brain.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Macrophage-colony stimulating factor (M-CSF) is implicated in HIV neuropathogenesis by modulating macrophage (MΦ) and microglia activation, increasing susceptibility to infection, and promoting virus production.
- M-CSF is expressed by perivascular MΦs in SIV encephalitis (SIVE) brain lesions, while IL-34 is found in parenchymal cells.
- Both M-CSF and IL-34 share the same receptor, cFMS.
Purpose of the Study:
- To investigate the roles of M-CSF and IL-34 in SIV encephalitis (SIVE) and their effects on macrophage activation.
- To determine if targeting cFMS signaling could be a therapeutic strategy for HIV infection in the brain.
Main Methods:
- Immunohistochemistry was used to examine M-CSF, IL-34, and CD163 expression in brain tissue from SIV-infected and non-infected rhesus macaques.
- Primary rhesus macaque and human monocytes were cultured with M-CSF or IL-34, with or without the cFMS inhibitor GW2580.
- Flow cytometry was used to analyze the effect of these cytokines on promoting an M2 monocyte/MΦ phenotype.
Main Results:
- In SIVE brains, M-CSF+ MΦs co-localized with CD163, a marker of M2 activation, while IL-34 did not significantly co-localize with CD163.
- M-CSF and IL-34 upregulate CD163 expression in primary monocytes, indicating M2 activation.
- This upregulation of CD163 by M-CSF and IL-34 was attenuated by the cFMS inhibitor GW2580.
Conclusions:
- Both M-CSF and IL-34 may promote or prolong M2 activation of MΦs and microglia in SIV-infected brains with encephalitis.
- cFMS signaling represents a potential therapeutic target for eradicating long-lived MΦ reservoirs of HIV infection in the brain and other tissues.
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