TNF inhibits catecholamine production from induced sympathetic neuron-like cells in rheumatoid arthritis and osteoarthritis in vitro

Markus Herrmann,Rainer H Straub,Zsuzsa Jenei-Lanzl,Sven Anders

doi:10.1038/s41598-018-27927-8

Abstract

Synovial adipose stem cells (sASC) can be differentiated into catecholamine-expressing sympathetic neuron-like cells to treat experimental arthritis. However, the pro-inflammatory tumor necrosis factor (TNF) is known to be toxic to catecholaminergic cells (see Parkinson disease), and this may prevent anti-inflammatory effects in inflamed tissue. We hypothesized that TNF exhibits inhibitory effects on human differentiated sympathetic tyrosine hydroxylase-positive (TH+) neuron-like cells. For the first time, iTH+ neuron-like sympathetic cells were generated from sACSs of rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Compared to untreated controls in both OA and RA, TNF-treated iTH+ cells demonstrated a weaker staining of catecholaminergic markers in cell cultures of RA/OA patients, and the amount of produced noradrenaline was markedly lower. These effects were reversed by etanercept. Exposure of iTH+ cells to synovial fluid of RA patients showed similar inhibitory effects. In mixed synovial cells, significant effects of TNF on catecholamine release were observed only in OA. This study shows that TNF inhibits iTH+ synovial cells leading to the decrease of secreted noradrenaline. This might be a reason why discovered newly appearing TH+ cells in the synovium are not able to develop their possible full anti-inflammatory role in arthritis.

Highlights

In previous studies, newly appearing tyrosine hydroxylase-positive (TH+) catecholamine-producing cells have been detected in synovial tissue of rheumatoid arthritis (RA) and osteoarthritis (OA) patients[1,2]
Morphological analysis with phase contrast microscopy demonstrated that iTH+ cells exhibited a neuron-like morphology with branches
Regarding iTH+ morphology, we observed qualitative differences between OA and RA: untreated RA iTH+ cells showed more elongated cell bodies and less branching compared to OA iTH+ cells, but cell-to-cell contacts were still visible (Fig. 2B,C untreated)

Summary

Introduction

Newly appearing tyrosine hydroxylase-positive (TH+) catecholamine-producing cells have been detected in synovial tissue of rheumatoid arthritis (RA) and osteoarthritis (OA) patients[1,2] Catecholamines, such as noradrenaline (NA) are able to mediate anti-inflammatory effects in RA depending on concentration and targeted receptor subtype (it is β2-adrenergic)[3,4]. The anti- inflammatory character of these TH+ cells has been demonstrated in vivo by adoptive transfer of generated TH+ cells in the collagen type II-induced arthritis model in mice[5] Generation of these TH+ cells might be possible using synovial adipose stem cells (sASC), because mesenchymal stem cells can differentiate into sympathetic neuron-like cells[5,6,7,8]. If TNF interferes with catecholamine production by inhibiting TH in synovial cells, this would be a proinflammatory signal due to the anti-inflammatory role of catecholamines at high concentrations through β2-adrenergic receptors[3,4]

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