Our objective was to investigate sympathetic and sensory nerve fibers in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) in relation to histological inflammation and synovial cytokine and norepinephrine (NE) secretion. Immunohistochemistry was used to detect nerve fibers and inflammatory parameters. A superfusion technique of synovial tissue pieces was used to investigate cytokine and NE secretion. In RA, we detected 0.2 +/- 0.04 tyrosine hydroxylase-positive (TH-positive=sympathetic) nerve fibers/mm2 as compared to 4.4 +/- 0. 8 nerve fibers/mm2 in OA (P<0.001). In RA, there was a negative correlation between the number of TH-positive nerve fibers and inflammation index (RRank=-0.705, P=0.002) and synovial IL-6 secretion (RRank=-0.630, P=0.009), which was not found in OA. Substance P-positive (=sensory) nerve fibers were increased in RA as compared to OA (3.5+/-0.2 vs. 2.3+/-0.3/mm2, P=0.009). Despite lower numbers of sympathetic nerve fibers in RA than in OA, NE release was similar at baseline (RA vs. OA: 152+/-36 vs. 106+/-21 pg/ml, n.s.). Basal synovial NE secretions correlate with the number of TH-positive CD 163+ synovial macrophages (RA: RRank=0.622, P=0.031; OA: RRank=0.299, n.s.), and synovial macrophages have been shown to produce NE in vitro. Whereas sympathetic innervation is reduced, sensory innervation is increased in the synovium from patients with longstanding RA when compared to the synovium from OA patients. The differential patterns of innervation are dependent on the severity of the inflammation. However, NE secretion from the synovial tissue is maintained by synovial macrophages. This demonstrates a loss of the influence of the sympathetic nervous system on the inflammation, accompanied by an up-regulation of the sensory inputs into the joint, which may contribute to the maintenance of the disease.

ObjectiveThe presence of selective sympathetic nerve repellents, i.e., semaphorins, may be responsible for the observed reduction of sympathetic innervation in the synovial tissue of patients with rheumatoid arthritis (RA). This study was undertaken to investigate the presence of different semaphorins in synovial tissue of patients with RA, patients with osteoarthritis (OA), and control subjects without inflammation.MethodsIn situ hybridizations with digoxigenin‐labeled RNA probes directed against different semaphorins were performed. The presence of semaphorin 3C (S3C) in the synovial tissue of 10 RA, 10 OA, and 5 control subjects was investigated using a polyclonal antiserum directed against S3C.ResultsAll in situ hybridizations revealed the presence of S3C messenger RNA, but no other investigated semaphorin (i.e., against primary afferent sensory nerve fibers), in the synovial tissue of RA and OA patients. Immunohistologic double staining demonstrated that macrophages and fibroblasts were positive for S3C protein. Quantitative analysis of S3C protein staining showed an increased density of S3C‐positive cells in the synovial tissue of RA patients (mean ± SEM 339 ± 65 cells/mm2) in comparison with OA patients (168 ± 27/mm2; P = 0.031 versus RA) and controls (126 ± 26/mm2; P = 0.027 versus RA). Studies of the relationship between sympathetic nerve fiber density and S3C‐positive cell density in the tissue of all patients showed that RA patients generally had lower densities of sympathetic nerve fibers and higher densities of S3C‐positive cells than OA patients and control subjects.ConclusionThese findings suggest that S3C from macrophages and fibroblasts, which is selectively directed against sympathetic nerve fibers, could be one element responsible for reduced sympathetic innervation in RA tissue. The inability of sympathetic nerve fibers to reinnervate synovial tissue could contribute to the chronic nature of RA.

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Abstract:The CNS modulates immune cells by direct synaptic-like contacts in the brain and at peripheral sites, such as lymphoid organs. To study the nerve-macrophage communication, a superfusion method was used to investigate cotransmission of neuropeptide Y (NPY) with norepinephrine (NE), with interleukin (IL)-6 secretion used as the macrophage read-out parameter. Spleen tissue slices spontaneously released NE, NPY, and IL-6 leading to a superfusate concentration at 3-4 h of 1 nM, 10 pM, and 120 pg/ml, respectively. Under these conditions, NPY dose-dependently inhibited IL-6 secretion with a maximum effect at 10 Ϫ10 M ( p ϭ 0.012) and 10 Ϫ9 M ( p Ͻ 0.001). Simultaneous addition of NPY at 10 Ϫ9 M and the ␣2-adrenergic agonist p-aminoclonidine further inhibited IL-6 secretion ( p Ͻ 0.05). However, simultaneous administration of NPY at 10 Ϫ9 M and the ␤-adrenergic agonist isoproterenol at 10 Ϫ6 M or NE at 10 Ϫ6 M significantly increased IL-6 secretion ( p Ͻ 0.005). To objectify these differential effects of NPY, electrical field stimulation of spleen slices was applied to release endogenous NPY and NE. Electrical field stimulation markedly reduced IL-6 secretion, which was attenuated by the NPY Y1 receptor antagonist BIBP 3226 (10 Ϫ7 M, p ϭ 0.039; 10 Ϫ8 M, p ϭ 0.035). This indicates that NPY increases the inhibitory effect of endogenous NE, which is mediated at low NE concentrations via ␣-adrenoceptors. Blockade of ␣-adrenoceptors attenuated electrically induced inhibition of IL-6 secretion ( p Ͻ 0.001), which was dosedependently abrogated by BIBP 3226. This indicates that under blockade of ␣-adrenoceptors endogenous NPY supports the stimulating effect of endogenous NE via ␤-adrenoceptors. These experiments demonstrate the ambiguity of NPY, which functions as a cotransmitter of NE in the nerve-macrophage interplay. Key Words: Neuropeptide Y-Norepinephrine-Neuroimmune interactionSpleen-Macrophage-Cytokines. J. Neurochem. 75, 2464Neurochem. 75, -2471Neurochem. 75, (2000.Neuropeptide Y (NPY) is a peptide with 36 amino acid residues that was isolated originally from the brain . NPY forms a family of peptides together with peptide YY and pancreatic polypeptide.These peptides have been found in endocrine cells of the gastrointestinal tract (Larsson et al., 1976;Lundberg et al., 1982) and also in neurons of the brainstem (Lundberg et al., 1984). With respect to NPY, a major portion of NPY-immunoreactive nerves in peripheral organs represents classical sympathetic fibers where NPY coexists with norepinephrine (NE) (Ekblad et al., 1984). There is evidence that NPY is stored in large vesicles of the nerve terminal together with NE, whereas small vesicles contain NE but no NPY (Fried et al., 1985). NPY makes direct vasoconstriction, increases effects of different vasoconstrictors, and inhibits some vasorelaxant agents (Hakanson et al., 1986;Itoi et al., 1986;Donoso et al., 1997). NPY is necessary for constriction of the ductus deferens (Stjärne et al., 1986), to increase intracellular Ca 2ϩ (Erdbrugger et al., 1993), to ...

Corticosteroids (CS) and norepinephrine (NE) support each other's biological effects. Thus, deficiency of cortisol and reduced synovial sympathetic innervation (SSI) may be proinflammatory in rheumatoid arthritis (RA). This study tested the anti-inflammatory cooperativity of CS and NE in human RA synovial tissue. In an in vivo study, 32 patients with RA (with prior CS therapy/without SSI: n=7; without prior CS therapy/with SSI: 6; with prior CS therapy/with SSI: 19) were investigated for synovial inflammation. In an in vitro study with synoviocytes from RA and OA patients, the separate and combined effects of cortisol and NE were studied. In the in vivo study, patients with prior CS therapy/with SSI showed lower secretion of synovial IL-8 than the other groups, lower synovial density of T cells and macrophages, and lower overall inflammation. In the in vitro study, a cooperative suppressive effect of NE (10(-6) M to 10(-8) M) and cortisol (10(-6) M and 10(-7) M) on secretion of IL-8 and TNF from primary early culture mixed RA synoviocytes was observed. This cooperative effect was not observed in OA synoviocytes. In the same RA and OA patients, the cooperative effect was lost in 3rd passage synovial fibroblasts. This study demonstrates the cooperativity of cortisol and NE for inhibition of proinflammatory mediators produced in the synovial tissue of RA patients. These results underscore that coupling of an efficient secretion of systemic cortisol together with local production of NE is important in order to lower synovial inflammation.

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Reports on patients with hemiparalysis indicate the importance of the nervous system for the pathophysiology of rheumatoid arthritis (RA) or osteoarthritis (OA). Norepinephrine (NE) and opioids seem to be more antiinflammatory neurotransmitters whereas substance P is proinflammatory. The study aimed to investigate the direct noradrenergic nerve-immune cell interaction in human synovial membrane. We used a recently developed superfusion technique with electrical stimulation of synovial membrane to elicit local NE from synovial membrane slices. The readout parameter of synovial immune cells was interleukin-6 (IL-6). IL-6 was spontaneously secreted from RA and OA synovial membranes. Electrical field stimulation intensively reduced IL-6 secretion. In patients with OA or RA, this electrically induced reduction of IL-6 secretion was not significantly changed by alpha- or beta-adrenergic antagonists. The study demonstrates that local endogenous NE seem to play a minor role, which may be due to a depletion of NE or loss of noradrenergic fibers during chronic RA and OA.

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