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

Abstract

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 catecholamine-producing cells can be depleted by 6-hydroxydopamine (6-OHDA) during the early and late phases of CIA in vivo. 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. 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. 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.