Department of Immunology, UT Southwestern Medical Center, Dallas, TX, United States.
Department of Immunology, UT Southwestern Medical Center, Dallas, TX, United States; Howard Hughes Medical Institute, United States.
Brain Behav Immun. 2018 Nov;74:176-185. doi: 10.1016/j.bbi.2018.09.004. Epub 2018 Sep 5.
The mammalian nervous system communicates important information about the environment to the immune system, but the underlying mechanisms are largely unknown. Secondary lymphoid organs are highly innervated by sympathetic neurons that secrete norepinephrine (NE) as the primary neurotransmitter. Immune cells express adrenergic receptors, enabling the sympathetic nervous system to directly control immune function. NE is a potent immunosuppressive factor and markedly inhibits TNF-α secretion from innate cells in response to lipopolysaccharide (LPS). In this study, we demonstrate that NE blocks the secretion of a variety of proinflammatory cytokines by rapidly inducing IL-10 secretion from innate cells in response to multiple Toll-like receptor (TLR) signals. NE mediated these effects exclusively through the β2-adrenergic receptor (ADRB2). Consequently, Adrb2 animals were more susceptible to L. monocytogenes infection and to intestinal inflammation in a dextran sodium sulfate (DSS) model of colitis. Further, Adrb2 animals rapidly succumbed to endotoxemia in response to a sub-lethal LPS challenge and exhibited elevated serum levels of TNF-α and reduced IL-10. LPS-mediated lethality in WT animals was rescued by administering a β 2-specific agonist and in Adrb2 animals by exogenous IL-10. These findings reveal a critical role for ADRB2 signaling in controlling inflammation through the rapid induction of IL-10. Our findings provide a fundamental insight into how the sympathetic nervous system controls a critical facet of immune function through ADRB2 signaling.
哺乳动物的神经系统将有关环境的重要信息传递给免疫系统，但潜在的机制在很大程度上尚不清楚。次级淋巴器官高度受交感神经元支配，交感神经元分泌去甲肾上腺素（NE）作为主要神经递质。免疫细胞表达肾上腺素能受体，使交感神经系统能够直接控制免疫功能。NE 是一种有效的免疫抑制因子，可显著抑制脂多糖（LPS）刺激下先天细胞 TNF-α 的分泌。在这项研究中，我们证明 NE 通过先天细胞对多种 Toll 样受体（TLR）信号的快速反应迅速诱导 IL-10 分泌，从而阻断多种促炎细胞因子的分泌。NE 通过β2-肾上腺素能受体（ADRB2）介导这些作用。因此，Adrb2 动物在单核细胞增多性李斯特菌感染和葡聚糖硫酸钠（DSS）结肠炎模型中更容易发生肠道炎症。此外，Adrb2 动物在对亚致死 LPS 挑战的反应中迅速死于内毒素血症，并表现出 TNF-α 血清水平升高和 IL-10 降低。在 WT 动物中，用β2 特异性激动剂和在 Adrb2 动物中用外源性 IL-10 挽救 LPS 介导的致死性。这些发现揭示了 ADRB2 信号在通过快速诱导 IL-10 控制炎症方面的关键作用。我们的发现为交感神经系统如何通过 ADRB2 信号控制免疫功能的关键方面提供了基本的认识。
