Supplementary Material for: Chronic effects of the sympathetic nervous system in inflammatory models

The immune system is embedded in a network of regulatory systems to keep homeostasis in case of an immunologic challenge. Neuroendocrine immunologic research revealed several aspects of these interactions over the past decades, e.g. between the autonomic nervous system and the immune system. This review will focus on evidence revealing the role of the sympathetic nervous system (SNS) in chronic inflammation, like colitis, multiple sclerosis, systemic sclerosis, lupus erythematodes, and arthritis with a focus on animal models supported by human data. A theory of the contribution of the SNS in chronic inflammation will be presented that spans these disease entities. One major finding is the biphasic nature of the sympathetic contribution to inflammation with proinflammatory effects until the point of disease outbreak and mainly anti-inflammatory influence thereafter. Since sympathetic nerve fibers are lost from sites of inflammation during inflammation, local cells and immune cells achieve the capability to endogenously produce catecholamines to fine-tune the inflammatory response independent of brain control. On a systemic level, it has been shown across models that the SNS is activated in inflammation as opposed to the parasympathetic nervous system. Permanent overactivity of the SNS contributes many of the known disease sequelae. One goal of neuroendocrine immune research is defining new therapeutic targets. In this respect, it will be discussed that at least in arthritis, it might be beneficial to support β-adrenergic and inhibit α-adrenergic activity besides restoring autonomic balance. Overall, in the clinical setting we now need controlled interventional studies to successfully translate the theoretical knowledge into benefits for patients.免疫系统嵌入于一套调控网络之中，以在遭遇免疫挑战时维持内稳态（homeostasis）。近数十年来，神经内分泌免疫学研究揭示了这些互作的诸多层面，例如自主神经系统（autonomic nervous system）与免疫系统间的调控交互。本综述将聚焦于揭示交感神经系统（sympathetic nervous system, SNS）在慢性炎症中作用的相关证据，所涉疾病包括结肠炎、多发性硬化、系统性硬化症、红斑狼疮与关节炎，且将重点探讨以人类数据佐证的动物模型相关研究。本综述将提出一套覆盖上述疾病范畴的SNS在慢性炎症中作用机制的理论框架。核心发现之一是SNS对炎症的调控具有双相特性：在疾病爆发前呈现促炎效应，而在疾病爆发后则主要发挥抗炎作用。由于炎症过程中交感神经纤维会从炎症位点流失，局部细胞与免疫细胞可获得内源性合成儿茶酚胺（catecholamines）的能力，从而在不依赖中枢调控的情况下精准调节炎症应答。在系统层面，多项模型研究均表明，与副交感神经系统（parasympathetic nervous system）不同，炎症状态下SNS会被激活。SNS的持续性过度激活会引发诸多已知的疾病后遗症。神经内分泌免疫学研究的目标之一，便是确立全新的治疗靶点。就此而言，本综述将探讨：至少在关节炎的治疗中，除了恢复自主神经平衡外，增强β肾上腺素能（β-adrenergic）活性并抑制α肾上腺素能（α-adrenergic）活性或可带来临床获益。总体而言，当前临床领域亟需开展对照性干预研究，以成功将理论认知转化为惠及患者的临床实践。