Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

Nickoleta Delivanoglou,Constantina Simeonidou,Evangelia Kesidou,Olga Touloumi,Ioannis Charalampopoulos,Nikolaos Grigoriadis,Marina Boziki,Evangelia Nousiopoulou,Roza Lagoudaki,Paschalis Theotokis,Nikolina Dafi

doi:10.1186/s12974-020-1708-9

Abstract

BackgroundNerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and pan-neurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. There are only few studies with inconclusive results concerning the expression pattern and role of NGF, TrkA, and p75NTR (NGF system) under the neuroinflammatory conditions in multiple sclerosis (MS) and its mouse model, the experimental autoimmune encephalomyelitis (EAE). The aim of this study is to investigate the temporal expression in different cell types of NGF system in the central nervous system (CNS) during the EAE course.MethodsEAE was induced in C57BL/6 mice 6–8 weeks old. CNS tissue samples were collected on specific time points: day 10 (D10), days 20–22 (acute phase), and day 50 (chronic phase), compared to controls. Real-time PCR, Western Blot, histochemistry, and immunofluorescence were performed throughout the disease course for the detection of the spatio-temporal expression of the NGF system.ResultsOur findings suggest that both NGF and its receptors, TrkA and p75NTR, are upregulated during acute and chronic phase of the EAE model in the inflammatory lesions in the spinal cord. NGF and its receptors were co-localized with NeuN+ cells, GAP-43+ axons, GFAP+ cells, Arginase1+ cells, and Mac3+ cells. Furthermore, TrkA and p75NTR were sparsely detected on CNPase+ cells within the inflammatory lesion. Of high importance is our observation that despite EAE being a T-mediated disease, only NGF and p75NTR were shown to be expressed by B lymphocytes (B220+ cells) and no expression on T lymphocytes was noticed.ConclusionOur results indicate that the components of the NGF system are subjected to differential regulation during the EAE disease course. The expression pattern of NGF, TrkA, and p75NTR is described in detail, suggesting possible functional roles in neuroprotection, neuroregeneration, and remyelination by direct and indirect effects on the components of the immune system.

Highlights

Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and panneurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system
P75NTR-Messenger RNA (mRNA) showed an increased expression at the acute and chronic phase ((1.4-fold) (p = 0.0234) and (2-fold) (p < 0.0001) respectively). Pan-neurotrophin receptor p75 (p75NTR) to TrkA ratio was found decreased at the acute and the chronic phase compared to control group (0.3-fold, p < 0.0001, and 0.5-fold, p = 0.0034, respectively) (Additional file 1: Figure S1B)
NGF acts protectively in the context of protective autoimmunity, where the body develops mechanisms to cope with central nervous system (CNS) damage by restricting and controlling the degeneration and/or promoting the regeneration [81, 82]. By this study, both the neuroprotective and antiinflammatory role of the NGF mediated by its tworeceptor system, TrkA and p75NTR, are highlighted during the destructive inflammatory attack of the autoimmune response in our Oligodendrocyte myelin glycoprotein (MOG)-EAE model

Summary

Introduction

Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and panneurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. In addition to the classical paradigm of neuroinflammation representing a devastating process for the CNS, accumulating evidence support its beneficial side and even neuroprotective action [1,2,3,4,5,6]. As far as it concerns the autoimmune diseases such as multiple sclerosis (MS), the related mechanisms are more complicated since autoimmunity involves the orchestrated attack of the peripheral immune system to the CNS [7]. When we consider about CNS homeostasis and neuroprotection, at the top of the list are the neurotrophic factors that mediate their actions through membrane receptors. NGF system signaling mediates neurite outgrowth, regulates sodium channel function, exerts prosurvival effects, and controls cell proliferation and differentiation [19,20,21,22,23,24]

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