The effects of painless nerve growth factor on human microglia polarization

Abstract

Previous studies in the rat suggest that microglial cells represent a potential druggable target for nerve growth factor (NGF) in the brain. The painless human Nerve Growth Factor (hNGFp) is a recombinant mutated form of human nerve growth factor (hNGF) that shows identical neurotrophic and neuroprotective properties of wild-type NGF but displays at least 10-fold lower algogenic activity. From the pharmacological point of view, hNGFp is a biased tropomyosin receptor kinase A (TrkA) agonist and displays a significantly lower affinity for the p75 neurotrophin receptor (p75NTR). This study aimed to evaluate the expression of TrkA and p75NTR NGF receptors in two different human microglia cell lines, and to investigate the effects of hNGFp and wild-type NGF (NGF) on L-arginine metabolism, taken as a marker of microglia polarization. Both NGF receptors are expressed in human microglia cell lines and are effective in transducing signals triggered by NGF and hNGFp. The latter and, to a lesser extent, NGF inhibit cytokine-stimulated inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in these cells. Conversely NGF but not hNGFp stimulates arginase-mediated urea production.

mTOR Inhibition Is Effective against Growth, Survival and Migration, but Not against Microglia Activation in Preclinical Glioma Models

“…Our group has previously investigated the L-arginine (L-ARG) metabolic pathways in microglial cells, taken as a marker of microglia polarization [ 10 , 31 , 32 , 33 , 34 ]. Here we tested the effects of Rapa and SAP on nitrite and urea production, considered as end-products of the L-ARG metabolism and indicators of M1 or M2 microglia polarization, respectively.…”

“…Different phenotypes may be present within the tumor [ 13 ], but microglia cells express mostly pro-tumor markers, defined as M2-profile. To investigate the profile of microglia activation, our group focuses on the analysis of the L-arginine (L-ARG) metabolic pathways [ 10 , 30 , 31 , 32 , 33 ]. In fact, L-ARG is a substrate for two different enzymes, arginase (ARG) and oxide nitric synthase (iNOS): L-ARG catabolism, through iNOS, produces nitric oxide (NO) and L-citrulline, whereas its catabolism via ARG yields urea and ornithine.…”

Cerebrospinal fluid level of proNGF as potential diagnostic biomarker in patients with frontotemporal dementia

“…Similarly, the prominent role of neuroinflammation in the pathogenesis of AD is largely recognized ( Kitazawa et al, 2004 ; DiSabato et al, 2016 ; Tischer et al, 2016 ; Leng and Edison, 2021 ). On the other hand, NGF and proNGF regulate immune response both in periphery ( Williams et al, 2015 ) and in CNS ( De Simone et al, 2007 ; Capsoni et al, 2011 ; D’Onofrio et al, 2011 ; Rizzi et al, 2018 ; Lisi et al, 2022 ). Indeed, proNGF is expressed by murine and human astrocytes ( Pedraza et al, 2005 ; Volosin et al, 2006 , 2008 ; Domeniconi et al, 2007 ) and an increase in proNGF expression and secretion was reported in response to several cases of insults ( Volosin et al, 2006 ; Domeniconi et al, 2007 ; Cheng et al, 2020 ), while NGF acts on microglia, steering it toward a neuroprotective and anti-inflammatory phenotype ( Rizzi et al, 2018 ; Lisi et al, 2022 ).…”