title: Role for cFMS in maintaining alternative macrophage polarization in SIV infection: implications for HIV neuropathogenesis.
abstract: 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.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, MERB, Room 748, Philadelphia, PA, 19140, USA. lindsey.gerngross@temple.edu.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Gerngross
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, MERB, Room 748, Philadelphia, PA, 19140, USA. lehmicke@temple.edu.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Lehmicke
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, MERB, Room 748, Philadelphia, PA, 19140, USA. aghilas.belkadi@temple.edu.
authors.forename: Aghilas
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, MERB, Room 748, Philadelphia, PA, 19140, USA. tlfsmith@temple.edu.
authors.forename: Tracy
authors.initials: T
authors.lastname: Fischer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology*; D008253:Macaca mulatta; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000473:pathology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D066127:White Matter / Q000378:metabolism
chemical_list: D016207:Cytokines; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor