title: Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation.
abstract: Macrophage and microglial activation by HIV in the central nervous system (CNS) triggers the secretion of soluble factors which damage neurons. Therapeutic approaches designed to restore cognitive function by suppressing this inflammatory activity have not yet been successful. Recent studies have indicated that the phenotype of macrophages is differentially controlled by the mature and pro form of nerve growth factor. These cells therefore may be highly responsive to the imbalance in pro versus mature neurotrophins often associated with neurodegenerative diseases. In this study we evaluated the interactions between neurotrophins and HIV induced macrophage activation. HIV stimulation of macrophages induced a neurotoxic phenotype characterized by the expression of podosomes, suppression of calcium spiking and increased neurotoxin production. The secretome of the activated macrophages revealed a bias toward anti-angiogenic like activity and increased secretion of MMP-9. Co-stimulation with NGF and HIV suppressed neurotoxin secretion, increased calcium spiking, suppressed podosome expression and reversed 86% of the proteins secreted in response to HIV, including MMP-9 and many growth factors. In contrast, co-stimulation of macrophages with proNGF not only failed to reverse the effects of HIV but increased the neurotoxic phenotype. These differential effects of proNGF and NGF on HIV activation provide a potential novel therapeutic avenue for controlling macrophage activation in response to HIV.
authors.affiliation: Department of Neurology, CB #7025, University of North Carolina, 6109F Neuroscience Research Building, 115 Mason Farm Road, Chapel Hill, NC, 27599, USA.|Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Williams
authors.affiliation: Department of Neurology, CB #7025, University of North Carolina, 6109F Neuroscience Research Building, 115 Mason Farm Road, Chapel Hill, NC, 27599, USA.|Center for Science and Mathematics Education, Stony Brook University, Stony Brook, NY, 11794, USA.
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Killebrew
authors.affiliation: Department of Neurology, CB #7025, University of North Carolina, 6109F Neuroscience Research Building, 115 Mason Farm Road, Chapel Hill, NC, 27599, USA.|US Food and Drug Administration, Rockville, MD, 20852, USA.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Clary
authors.affiliation: Department of Neurology, CB #7025, University of North Carolina, 6109F Neuroscience Research Building, 115 Mason Farm Road, Chapel Hill, NC, 27599, USA. meekerr@neurology.unc.edu.|Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, 27599, USA. meekerr@neurology.unc.edu.
authors.forename: Rick B
authors.initials: RB
authors.lastname: Meeker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005434:Flow Cytometry; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000821:virology*; D020932:Nerve Growth Factor / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D017077:Culture Media, Conditioned; D020932:Nerve Growth Factor
keywords: Actin; Calcium; Inflammation; Neuroprotection; TrkA; p75 neurotrophin receptor