Laboratory of Immunity and Infection, Department of Surgery, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103, USA.
FASEB J. 2011 Dec;25(12):4476-85. doi: 10.1096/fj.11-191007. Epub 2011 Aug 12.
The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of β2-adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either β2-knockout or lymphocyte-deficient nude mice. Unlike typical suppressor CD25(+) cells, the transfer of CD4(+)CD25(-) regulatory lymphocytes reestablishes the anti-inflammatory potential of the vagus nerve and β2-agonists to control inflammation in both β2-knockout and nude mice. β2-Agonists inhibit cytokine production in splenocytes (IC(50)≈ 1 μM) and prevent systemic inflammation in wild-type but not in β2-knockout mice. β2-Agonists rescue wild-type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti-inflammatory potential of β2-agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in β2-knockout mice. These results indicate that β2-adrenoceptors in regulatory lymphocytes are critical for the anti-inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.
神经系统经典地分为交感神经系统和副交感神经系统，它们相互对立以维持生理内稳态。在这里，我们报告说，这两个系统都集中在激活脾脏调节性淋巴细胞的β2-肾上腺素能受体上，以控制全身炎症。迷走神经刺激不能控制β2 基因敲除或淋巴细胞缺陷裸鼠的血清 TNF 水平。与典型的抑制性 CD25(+)细胞不同，CD4(+)CD25(-)调节性淋巴细胞的转移重建了迷走神经和β2-激动剂控制β2 基因敲除和裸鼠炎症的抗炎潜力。β2-激动剂抑制脾细胞中的细胞因子产生（IC(50)≈1μM），并防止野生型小鼠但不能防止β2 基因敲除小鼠发生全身炎症。β2-激动剂在临床相关的时间范围内将野生型小鼠从已建立的多微生物性腹膜炎中解救出来。调节性淋巴细胞重建了β2-激动剂控制全身炎症、器官损伤和β2 基因敲除小鼠致死性内毒素性休克的抗炎潜力。这些结果表明，调节性淋巴细胞中的β2-肾上腺素能受体对于副交感神经迷走神经的抗炎潜力至关重要，它们代表了败血症的一个潜在的药理靶点。
