Differential regulation of macrophage phenotype by mature and pro-nerve growth factor

Williams, Kimberly S.; Killebrew, Deirdre A.; Clary, Gillian; Seawell, Jaimie; Meeker, Rick B.

doi:10.1016/j.jneuroim.2015.05.016

Cited by 46 publications

(54 citation statements)

References 58 publications

(80 reference statements)

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“…ProNGF+HIV had no effect on phagocytosis compared to control or HIV-treated cells. This result was counterintuitive since previous studies had shown that a more ruffled phenotype is associated with phagocytic activity (Williams et al 2015). However, in the presence of …”

Section: Hiv Had No Effect On Phagocytic Activity In Hmdmmentioning

confidence: 76%

“…The neurotrophin receptors p75 NTR and TrkA have recently been shown to be robustly expressed on hMDM and monocytes (Williams et al 2015). To assess whether HIV could regulate the expression of p75 NTR and TrkA, hMDM were exposed to HIV virions for 1 h followed by flow cytometry analysis.…”

Section: P75 Ntr and Trka Expression In Response To Hivmentioning

confidence: 99%

“…Macrophages in culture show a low intrinsic rate of small calcium spike generation which is increased by NGF and decreased by proNGF (Williams et al 2015). HIV interactions with chemokine receptors have been shown to increase intracellular calcium in cultured human macrophages (Del Corno et al 2001) although the temporal pattern of calcium spiking was not evaluated.…”

Section: Hiv Suppressed Macrophage Calcium Activitymentioning

confidence: 99%

“…NGF was shown to increase calcium spiking, membrane ruffling, phagocytosis and secretion of growth factors and other proteins beneficial for neuronal support. Stimulation with proNGF, in contrast, suppressed calcium spiking and increased podosome formation, migration and secretion of neurotoxins (Williams et al 2015). Studies in HIV-infected humans have shown that neurotrophin levels are decreased in the brain compartment, suggesting a deficit in neurotrophin signaling (Meeker et al 2011), a scenario similar to other neurodegenerative diseases such as Alzheimer disease where decreases in the ratio of NGF to proNGF correlate with disease progression (Al-Shawi et al 2007;Mufson et al 2007;Capsoni et al 2011) (Kaul and Lipton 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies of cultured human monocyte-derived macrophages (hMDM) have shown that hMDM robustly express neurotrophin receptors TrkA and p75 NTR and respond differently to their respective ligands mature nerve growth factor (NGF) and its precursor, proNGF (Williams et al 2015). Exposure to NGF resulted in markedly different structural and functional phenotypes relative to proNGF, indicating that the peptides have distinct roles in the control of macrophage activation.…”

Section: Introductionmentioning

confidence: 99%

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Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

Williams¹,

Killebrew

Clary

et al. 2015

J Neuroimmune Pharmacol

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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.

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Section: Hiv Had No Effect On Phagocytic Activity In Hmdmmentioning

confidence: 76%

Section: P75 Ntr and Trka Expression In Response To Hivmentioning

confidence: 99%

Section: Hiv Suppressed Macrophage Calcium Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

Williams¹,

Killebrew

Clary

et al. 2015

J Neuroimmune Pharmacol

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NGF steers microglia toward a neuroprotective phenotype

Rizzi

Tiberi

Giustizieri

et al. 2018

Glia

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Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti‐inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aβ peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA‐mediated engulfment of Aβ by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aβ treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aβ‐induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex‐vivo setup of acute brain slices, we observed a similar increase in Aβ engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aβ accumulation pathologies, via its anti‐inflammatory activity on microglia.

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p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

Düsedau

Alexander

Figueiredo

et al. 2018

Glia

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Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75 NTR ) signaling. The p75 NTR is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75 NTR on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii ( T. gondii ) infection‐induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75 NTR upon infection in wild‐type mice. Although cell recruitment and phagocytic capacity of p75 NTRexonIV knockout (p75 −/− ) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75 −/− mice upregulated the production of the cytokines interleukin (IL)‐10, IL‐6 as well as IL‐1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75 NTR , were highly increased upon chronic infection in the brain of wild‐type and p75 −/− mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation‐induced changes in spine density were rescued in the p75 −/− mice. In conclusion, these findings indicate that neurotrophin signaling via the p75 NTR affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.

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Differential regulation of macrophage phenotype by mature and pro-nerve growth factor

Cited by 46 publications

References 58 publications

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

NGF steers microglia toward a neuroprotective phenotype

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

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Differential regulation of macrophage phenotype by mature and pro-nerve growth factor

Cited by 46 publications

References 58 publications

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

NGF steers microglia toward a neuroprotective phenotype

p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

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Product

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About

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation