Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital, Regensburg, Germany,
Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital, Regensburg, Germany.
Neuroimmunomodulation. 2020;27(1):58-68. doi: 10.1159/000508109. Epub 2020 Jul 1.
In arthritic mice, a sympathetic influence is proinflammatory from the time point of immunization until the onset of disease (days 0-32), but reasons are unknown. Disruption of the major anti-inflammatory pathway through Gαs-coupled receptors probably play a role. For example, noradrenaline cannot operate via anti-inflammatory β2-adrenoceptors but through proinflammatory α1/2-ad-renoceptors. This might happen, first, through a loss of sympathetic nerve fibers in inflamed tissue with low neurotransmitter levels (noradrenaline only binds to high-affinity α-adrenoceptors) and, second, through an alteration in G-protein receptor coupling with a predominance of α-adrenergic signaling. We hypothesized that both mechanisms play a role in the course of collagen type II-induced arthritis (CIA) in the spleen in mice.
In CIA mice, nerve fiber density in the spleen was quantified by immunohistochemistry techniques. The functional impact of sympathetic nerve fibers in the spleen was studied by a micro-superfusion technique of spleen slices with a focus on the secretion of IFN-γ and IL-6 (proinflammatory) and TGF-β (anti-inflammatory).
During CIA, sympathetic nerve fibers get increasingly lost from day14 until day 55 after immunization. The influence of electrically released noradrenaline diminishes in the course of arthritis. At all investigated time points (days 14, 32, and 55), only proinflammatory neuronal α-adrenergic effects on cytokine secretion were demonstrated (i.e., stimulation of IFN-γ and IL-6 and inhibition of TGF-β).
Sympathetic nerve fibers are rapidly lost in the spleen, and only proinflammatory α-adrenergic neuronal regulation of cytokine secretion takes place throughout the course of arthritis. These results support a predominance of a proinflammatory α-adrenergic sympathetic influence in arthritis.
在关节炎小鼠中，从免疫接种到疾病发作（第 0-32 天）的时间点，交感神经的影响是促炎的，但原因尚不清楚。通过 Gαs 偶联受体的主要抗炎途径的破坏可能发挥作用。例如，去甲肾上腺素不能通过抗炎的β2-肾上腺素受体发挥作用，而是通过促炎的α1/2-肾上腺素受体发挥作用。这可能首先发生在炎症组织中交感神经纤维的丢失，导致神经递质水平降低（去甲肾上腺素仅与高亲和力的α-肾上腺素受体结合），其次是 G 蛋白受体偶联的改变，导致α-肾上腺素能信号的优势。我们假设这两种机制都在胶原 II 诱导的关节炎（CIA）小鼠脾脏的病程中起作用。
在 CIA 小鼠中，通过免疫组织化学技术量化脾脏中的神经纤维密度。通过脾脏切片的微灌注技术研究了脾脏中交感神经纤维的功能影响，重点研究 IFN-γ 和 IL-6（促炎）和 TGF-β（抗炎）的分泌。
在 CIA 期间，从免疫后第 14 天到第 55 天，交感神经纤维逐渐丢失。电释放去甲肾上腺素的影响在关节炎过程中减弱。在所有研究的时间点（第 14、32 和 55 天），仅观察到促炎神经元α-肾上腺素能对细胞因子分泌的影响（即刺激 IFN-γ 和 IL-6，抑制 TGF-β）。
在关节炎过程中，脾脏中的交感神经纤维迅速丢失，只有促炎的α-肾上腺素能神经元调节细胞因子的分泌。这些结果支持了炎症中促炎的α-肾上腺素能交感神经影响的优势。
