Anti-inflammatorische Pfade der katecholaminergen, Tyrosinhydroxylase (TH) - positiven Zellen bei menschlicher und experimenteller Arthritis
Zusammenfassung der Projektergebnisse
During the last two decades, neuroendocrine immune interactions became more and more relevant in understanding pathophysiology of rheumatic diseases. In rheumatoid arthritis (RA), compared to osteoarthritis (OA), a massive loss of tyrosine hydroxylase-positive (TH+) nerve fibers and a clear increase of TH+ cells in inflamed synovial tissue of humans were found. The role of these TH+ cells was completely unclear that time. We demonstrated that different cells of the synovium (macrophages, fibroblasts, B cells, neutrophils, mast cells) express TH and can produce catecholamines in RA. Due to difficulties in TH+-cell separation, we analyzed mixed synoviocytes in further experiments. Mixed human synoviocytes express specific adrenoceptors (ARs), however, blockade of these receptors did not change secretion of TNF. This was a first indication that classical signaling through the β-adrenoceptor does not work. We were able to confirm the clear anti-inflammatory effect of TH+ cells in experimental arthritis using adoptively transferred TH+ cells, generated from mesenchymal stem cells (MSCs). Treatment of synovial cells with different receptor agonists and antagonists showed no typical GalphaS signaling and respective anti-inflammatory effects. This changed our goals completely. We demonstrated a clear defect of canonical GalphaS signaling in mixed synovial cells that was particularly relevant under hypoxia. In addition, TNF was an inhibitor of induced TH+ sympathetic cells. Since cell transplantation with TH+ cells might be a therapeutic option, TNF-induced inhibition of these cells must be viewed as drawback. TNF is most probably high in inflamed synovial tissue so that TH+ cells will possibly lose their antiinflammatory character. This might be different under other conditions with less inflammation.
Projektbezogene Publikationen (Auswahl)
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Increased expression of dopamine receptors in synovial fibroblasts from patients with rheumatoid arthritis: inhibitory effects of dopamine on interleukin-8 and interleukin-6. Arthritis Rheumatol 2014; 66(10):2685-93
Capellino S, Cosentino M, Luini A, Bombelli R, Lowin T, Cutolo M, Straub RH
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Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis. Ann Rheum Dis 2015; 74(2):444-51
Jenei-Lanzl Z, Capellino S, Kees F, Fleck M, Lowin T, Straub RH
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Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 recruitment in mixed RA synovial cells. Brain Behav Immun. 2015;50:266-274
Jenei-Lanzl Z, Zwingenberg J, Lowin T, Anders S, Straub RH
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A Promising New Approach for the Treatment of Inflammatory Pain: Transfer of Stem Cell-Derived Tyrosine Hydroxylase-Positive Cells. Neuroimmunomodulation. 2018;25(4):225-237
Ebbinghaus M, Jenei-Lanzl Z, Segond von Banchet G, Stangl H, Gajda M, Straub RH, Schaible HG
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TNF inhibits catecholamine production from induced sympathetic neuron-like cells in rheumatoid arthritis and osteoarthritis in vitro. Sci Rep. 2018;8(1):9645
Herrmann M, Anders S, Straub RH, Jenei-Lanzl Z
