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.

Equol, a Dietary Daidzein Gut Metabolite Attenuates Microglial Activation and Potentiates Neuroprotection In Vitro

“…In this study, Equol significantly increased neurite length and density relative to retinoic acid, demonstrating the strong neuroprotective efficacy of Equol in N2a cells. On the other hand, NGF, secreted by astrocytes, can repair inflammation-induced damage to neurons and prevent apoptotic neuronal cell death [61]. In this study, Equol substantially increased the secretion of NGF in C6 glioma cells, suggesting a neuroprotective effect.…”

Human Immunodeficiency Virus Promotes Mitochondrial Toxicity

“…Gp120 indirectly activates p75NTR by increasing the levels of the BDNF precursor protein, proBDNF (Bachis et al 2012), which, in turn, causes loss of dendritic spines (Bachis et al 2016) and negatively influences other forms of synaptic plasticity (Yang et al 2014). Small molecules like LM11A-31, which inhibit p75NTR (Pehar et al 2006), or blocking antibodies against p75NTR (Bachis et al 2012) are able to protect neurons from HIV-induced toxicity either by blocking calcium accumulation (Williams et al 2016), or reducing p75NTR-mediated activation of pro-apoptotic signal (Bachis et al 2012). A clear challenge in the field is to validate the data obtained in animal models to HAND subjects.…”

RME-based pharmacology: The inhibition of viral entry as therapeutic perspective in viral diseases including AIDS. Hypothesis updated and enlarged

“…Tentatively, some of them or a combination with antiretroviral therapy (ART) may possess a therapeutic value ing the keys to close the door for HIV-1 entry (62), thus being an additional state-of-the-ART in the therapy of AIDS and AIDS-related diseases, e.g. HIV-associated neurocognitive and cardiometabolic diseases (63)(64)(65)(66).…”