First appearance and location of catecholaminergic cells during experimental arthritis and elimination by chemical sympathectomy

Abstract

Objective. The sympathetic nervous system is proinflammatory in early collagen-induced arthritis (CIA) and antiinflammatory in late disease. In late arthritis, sympathetic innervation of synovial and lymphoid tissue is markedly reduced. Thus, its suggested antiinflammatory role is difficult to explain. We hypothesized that newly discovered catecholamine-producing (catecholaminergic) cells are targets of chemical sympathectomy. However, in CIA, the time point of appearance, the location, and the possible chemical elimination of catecholaminergic cells have not been studied. The purpose of this study was to investigate the emergence and location of catecholamine-producing and -storing cells in different organs and joints of mice after induction of CIA and to determine whether catecholamineproducing cells can be depleted by 6-hydroxydopamine (6-OHDA) during the early and late phases of CIA in vivo.Methods. The presence of cells positive for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT-2) was evaluated immunohistologically in the lymph nodes, thymus, bone marrow, spleen, and joints of control and arthritic mice. Density was evaluated at different time points after early and late chemical sympathectomy. 131 I-metaiodobenzylguanidine ( 131 I-MIBG) scintigraphy demonstrated functional activity of these cells in joint inflammation.Results. The density of TH؉ and VMAT-2؉ cells was highest after arthritis onset (from day 28 onward) and was observed to occur in the following sequence: lymph nodes, thymus, joints, bone marrow, and spleen. Even before arthritis onset (days 5-21), these cells were already more numerous, particularly in the draining lymph nodes, thymus, and joints. 131 I-MIBG scintigraphy demonstrated catecholamine-storing cells in inflammatory hot spots in the paw. Chemical sympathectomy strongly reduced the density of catecholaminergic cells in vitro and in vivo.Conclusion. After disease onset, catecholaminergic cells are particularly present in primary and secondary lymphoid organs and joints. Since catecholaminergic cells have been reported to have antiinflammatory properties in arthritis, the proinflammatory role played by chemical sympathectomy in late arthritis, as we previously determined, is probably dependent on catecholaminergic cell elimination.

Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis

“…Thus, the loss of sympathetic nerve fibres in inflamed tissue was interpreted as a pro-inflammatory event 2 7 28. Importantly, concomitant to the loss of sympathetic nerve fibres there appear newly formed cells that express TH, which we called TH + cells or catecholaminergic cells,9 10 but their role is unclear. While some authors hypothesised that these cells have pro-inflammatory activities,29 TH + cells might have anti-inflammatory capacities when neurotransmitter concentrations are high enough for β-adrenergic signalling 9…”

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: Impact of exogenous neuropeptide Y

“…Indirect evidence also shows neurotransmitter release from immune cells in response to electrical stimulation [24]. In fact, in face of the loss of sympathetic nerve fibers, which is a feature of many chronic inflammatory diseases [25], concomitant increase in tyrosine-hydroxylase positive immune cells has been demonstrated [26]. Considering the well-known splanchnic chronic low level inflammation in ascitic cirrhosis, it is tempting to speculate whether an enhanced infiltration with catecholaminergic immune cells may contribute to the increased PNSinduced NA release.…”

A Promising New Approach for the Treatment of Inflammatory Pain: Transfer of Stem Cell-Derived Tyrosine Hydroxylase-Positive Cells

“…While the CIA model is characterized by a substantial expression of endogenous TH + cells in the course of CIA in the spleen, the lymph nodes, and the inflamed joints [8], we detected only a transient expression of TH + cells in the AIA model in the acute phase. In the CIA model the appearance of TH + cells is thought to provide anti-inflammatory effects in a late phase of CIA in which TH-positive nerve fibers with anti-inflammatory effects become sparse in the joint.…”

“…Naturally occurring TH + cells were quantified according to the protocol from Capellino et al [8]. Lymph nodes, spleen, and knee joints were removed from AIA mice and fixed for 24 h with 3.7% PFA.…”

“…The TH + cells were shown to express a range of neuronal markers (TH, β-III-tubulin, and vesicular monoamine transporter 2 [VMAT-2]). Their number significantly increased in CIA, and they could be selectively depleted by sympathectomy with 6-hydroxydopamine [7, 8]. Cells exhibiting characteristics of TH + cells could be generated from murine bone marrow-derived stem cells (mesenchymal cells, MSC) and human synovial adipose stem cells [9, 10].…”