通过迷走神经依赖途径抑制 TGF-β产生纠正老年脓毒症大鼠的免疫抑制作用：人 ghrelin 和生长激素的作用。
Correction of immunosuppression in aged septic rats by human ghrelin and growth hormone through the vagus nerve-dependent inhibition of TGF-β production.
机构信息
Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.
Departments of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.
出版信息
Mol Med. 2020 Jul 16;26(1):71. doi: 10.1186/s10020-020-00195-x.
BACKGROUND
Co-administration of human ghrelin and growth hormone (GH) reverse immunosuppression in septic aged animals, but the mechanism remains elusive. Here, we hypothesize that ghrelin and GH co-treatment restores the immune response in aged septic rats by inhibiting the production of transforming growth factor-β (TGF-β), an immunoregulatory cytokine, through the vagus nerve.
METHODS
Male aged Fischer rats (22-23-month-old) were made septic by cecal ligation and puncture (CLP) with or without dissecting the vagus nerve (vagotomy). Human ghrelin and GH or vehicle (PBS) were administrated subcutaneously at 5 h post CLP. After 20 h of CLP, serum and spleens were harvested.
RESULTS
Serum TGF-β levels were increased in septic aged rats, while ghrelin and GH treatment significantly reduced its levels. Expression of TGF-β in the spleen was upregulated after sepsis, while ghrelin and GH treatment significantly inhibited its expression. TNF-α and IL-6 levels were significantly reduced after ex vivo LPS stimulation of splenocytes from rats that underwent CLP compared to sham rats; while these levels were significantly higher in splenocytes from ghrelin and GH-treated CLP rats compared to vehicle-treated CLP rats. Ghrelin and GH treatment reduced program death receptor-1 (PD-1) expression, increased human leukocyte antigen-DR (HLA-DR) expression, attenuated lymphopenia, and cleaved caspase-3 levels in the spleen of septic aged rats. Vagotomy diminished the beneficial effects of ghrelin and GH treatment in septic rats. In vitro, the addition of ghrelin, GH, or ghrelin and GH together had no effect on restoring immune response in splenocytes from CLP rats following LPS stimulation, indicating the requirement of the vagus nerve for ghrelin and GH's effect.
CONCLUSIONS
Ghrelin and GH attenuate immunosuppression in aged septic rats through the vagus nerve-dependent inhibition of TGF-β production.
背景
在脓毒症老年动物中，同时给予人 ghrelin 和生长激素（GH）可逆转免疫抑制，但机制尚不清楚。在这里，我们假设 ghrelin 和 GH 联合治疗通过迷走神经抑制免疫调节细胞因子转化生长因子-β（TGF-β）的产生，从而恢复老年脓毒症大鼠的免疫反应。
方法
通过盲肠结扎和穿刺（CLP）使雄性老年 Fischer 大鼠（22-23 月龄）发生脓毒症，同时或不分离迷走神经（迷走神经切断术）。在 CLP 后 5 小时，通过皮下给予人 ghrelin 和 GH 或载体（PBS）。CLP 后 20 小时，采集血清和脾脏。
结果
脓毒症老年大鼠血清 TGF-β水平升高，而 ghrelin 和 GH 治疗显著降低其水平。脾中 TGF-β的表达在脓毒症后上调，而 ghrelin 和 GH 治疗显著抑制其表达。与假手术大鼠相比，CLP 大鼠的脾细胞经 LPS 体外刺激后 TNF-α和 IL-6 水平显著降低；而 ghrelin 和 GH 治疗的 CLP 大鼠的脾细胞中这些水平明显高于载体治疗的 CLP 大鼠。ghrelin 和 GH 治疗降低程序性死亡受体-1（PD-1）表达，增加人白细胞抗原-DR（HLA-DR）表达，减轻脾淋巴细胞减少和半胱天冬酶-3 水平，减轻老年脓毒症大鼠的脾损伤。迷走神经切断术减弱了 ghrelin 和 GH 治疗在脓毒症大鼠中的有益作用。在体外，ghrelin、GH 或 ghrelin 和 GH 联合添加对 LPS 刺激后 CLP 大鼠脾细胞免疫反应的恢复没有影响，表明 ghrelin 和 GH 的作用需要迷走神经。
结论
ghrelin 和 GH 通过迷走神经依赖性抑制 TGF-β的产生来减轻老年脓毒症大鼠的免疫抑制。
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