NEUROTROPHIN-CHEMOKINE RECEPTOR INTERACTIONS ON MACROPHAGES REGULATE HIV NEUROPATHOGENESIS

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  • March 19, 2019
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  • Williams, Kimberly
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
Abstract
  • Invading perivascular macrophages and microglial cells play a pivotal role in the neuropathogenesis of Human Immunodeficiency Virus (HIV) associated neurological disorders. As with many neurodegenerative diseases, the activation of macrophages and microglia cells in the central nervous system (CNS) leads to the secretion of unknown neurotoxins and is thought to contribute heavily to neuronal damage. However, these cells are very dynamic with a wide range of functions including neuroprotection and repair. It has become increasingly clear that strategies to modulate specific phenotypes of these cells have substantial therapeutic potential. This thesis has identified a novel neurotoxic phenotype in human macrophages that extends beyond the classical M1 inflammatory or M2 anti-inflammatory activation categories often seen in the literature. Macrophage phenotypes that correlated with the secretion of neurotoxins assessed by measuring calcium dysregulation in neurons consisted of suppressed calcium spiking and the formation of polarized podosomes. We found that macrophages not possessing this neurotoxic phenotype showed increased ruffling of the membrane and increased calcium spikes. In neurodegenerative diseases, an imbalance in pro-neurotrophins versus mature neurotrophins have been observed, however the actions of pro-neurotrophins on macrophages have never been studied. We have shown that, similar to their opposing roles in neurons, proNGF signaling in macrophages stimulated the neurotoxic phenotype while mature NGF created a more neuroprotective phenotype which was dependent on TrkA. The neurotoxic phenotype was also driven by HIV in a p75NTR and CXCR4 dependent manner. Neurotrophin signaling was able to modulate the HIV neurotoxic phenotype by exacerbating neurotoxin production (proNGF) or partially restoring the non-toxic phenotype (NGF). This thesis for the first time identified an interaction between the neurotrophin receptors p75NTR and TrkA and the HIV co-receptor CXCR4 through the use of co-immunoprecipitation techniques, which may be involved in the regulation of neurotoxic phenotypes. NGF co-stimulation with HIV increased CXCR4 phosphorylation and association with G-protein receptor kinase 2 (GRK2). This contrasted with the decrease in GRK2/CXCR4 complexes seen with HIV stimulation alone. Phosphorylated CXCR4 (pCXCR4) was found in overlapping domains with p75NTR and TrkA, which was downregulated by HIV. NGF was able to restore the p75NTR/pCXCR4 co-localization and partially restored pCXCR4/TrkA co-localization. This data indicated that NGF suppressed the HIV neurotoxic phenotype by facilitating phosphorylation of the HIV co-receptor CXCR4 while proNGF enhanced HIV effects. Overall, these studies have identified novel effects of the neurotrophins on macrophages that may provide new therapeutic avenues for the control of toxic macrophage phenotypes seen in HIV associated neurocognitive disorders and other neuroinflammatory diseases.
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  • In Copyright
Advisor
  • Meeker, Rick B.
  • Harry, G. Jean
  • Deshmukh, Mohanish
  • McCarthy, Ken D.
  • Eron, Joseph
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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  • There are no restrictions to this item.
Date uploaded
  • June 23, 2015

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