NGF steers microglia toward a neuroprotective phenotype

Abstract

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.

How to reprogram microglia toward beneficial functions

“…The classical neurotrophin NGF, through activation of Trk‐A receptors was recently shown to steer microglia toward a neuroprotective and anti‐inflammatory phenotype (Rizzi et al, ) (Figure ), being particularly effective in reverting the pro‐inflammatory state of microglia induced by β‐amyloid. Importantly, the receptor signaling activated by NGF in primary culture and ex vivo not only regulates a number of microglia activities, such as cytokine/chemokine secretion, motility, phagocytosis, and degradative pathways but also controls microglia–neuron interaction, protecting neurons against Aβ‐induced spine alterations and synaptic dysfunction.…”

“…Neuropeptides and neurotrophins acting through specific receptors are able to modulate microglial response by inhibiting the release of inflammatory mediators while favoring development of an alternative activation program (Carniglia et al, 2017;Rizzi et al, 2018). Specifically, the melanocortins α-MSH and NDP-MSH, both exerting their actions through G protein-coupled receptors (GPCRs), were found to induce expression of the metabolic enzyme Arg1 in microglia in the retina (Kawanaka & Taylor, 2011) and in rat primary culture (Carniglia, Durand, Caruso, & Lasaga, 2013).…”

“…The classical neurotrophin NGF, through activation of Trk-A receptors was recently shown to steer microglia toward a neuroprotective and anti-inflammatory phenotype (Rizzi et al, 2018) (Figure 1), being particularly effective in reverting the pro-inflammatory state of FIGURE 1 Schematic representation of receptors and signaling pathways mainly contributing to anti-inflammatory polarization of microglia. Stimulation of histamine receptors H1R and H4R induces persistent ERK1/2 phosphorylation, that leads to pNF-κB downregulation and reduces the expression of NADPH oxidase 2 (NOX2), dampening pro-inflammatory responses.…”

Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

“…Due to its neuroprotective action and its potential as a treatment for neurodegenerative and inflammatory conditions, neurotrophins have been either used themselves as treatment or mimicked in many studies over the past few years [64][65][66][67][68]. NGF therapeutic application is limited because of its poor plasma stability, inability to cross the blood brain barrier and the pleiotropic actions derived from its concomitant connection to different receptors.…”

Chronic electrical stimulation reduces hyperalgesia and associated spinal changes induced by peripheral nerve injury

“…Transverse sections were cut at 25 μm thickness on a cryostat and mounted on slides. Sections were blocked with specific serum and incubated overnight with primary antibodies in 0.3% Triton X‐100 in PBS, for staining microglial cells (anti‐Iba1, goat, 1:200, Abcam ), astrocytes (anti‐GFAP, rabbit, 1:500, DakoCytomation ), adrenergic receptors (anti‐β 2 receptors, rabbit, 1:500, Santa Cruz ), K + ‐Cl − cotransporter 2 (anti‐KCC2, rabbit, 1:500, Millipore ) and γ‐aminobutyric acid (anti‐GABA, rabbit, 1:500, Sigma–Aldrich ). The following day, sections were incubated for two hours with Alexa Fluor 488 and/or Alexa Fluor 594 conjugated secondary antibodies (1:200, Life Technologies).…”