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.
Subject(s)
HIV Infections/metabolism , Macrophage Activation/physiology , Macrophages/metabolism , Macrophages/virology , Nerve Growth Factor/metabolism , Animals , Cells, Cultured , Culture Media, Conditioned/pharmacology , Flow Cytometry , Humans , Immunohistochemistry , Immunoprecipitation , Rats , Rats, Long-EvansABSTRACT
To characterize the role of neurotrophin receptors on macrophages, we investigated the ability of nerve growth factor (NGF) and its precursor, proNGF, to regulate human macrophage phenotype. The p75 neurotrophin receptor (p75(NTR)) and TrkA were concentrated within overlapping domains on membrane ruffles. NGF stimulation of macrophages increased membrane ruffling, calcium spiking, phagocytosis and growth factor secretion. In contrast, proNGF induced podosome formation, increased migration, suppressed calcium spikes and increased neurotoxin secretion. These results demonstrate opposing roles of NGF and proNGF in macrophage regulation providing new avenues for pharmacological intervention during neuroinflammation.
Subject(s)
Macrophages/physiology , Nerve Growth Factor/pharmacology , Phenotype , Protein Precursors/pharmacology , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cells, Cultured , Female , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/physiology , Macrophages/drug effects , Rats , Rats, Long-EvansABSTRACT
As research subjects, cats have contributed substantially to our understanding of biological systems, from the development of mammalian visual pathways to the pathophysiology of feline immunodeficiency virus as a model for human immunodeficiency virus. Few studies have evaluated humane methods for managing cats in laboratory animal facilities, however, in order to reduce fear responses and improve their welfare. The authors describe a behavioral protocol used in their laboratory to condition cats to handling and transport. Such behavioral conditioning benefits the welfare of the cats, the safety of animal technicians and the quality of feline research data.
