Priyanka Hannah P, Thiyagaraj A, Krithika G, Nair R S, Hopper W, ThyagaRajan S
Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India.
Inspire Lab, Institute of Advanced Research in Health Sciences, Tamil Nadu Government Multi Super Specialty Hospital, Chennai, Tamil Nadu, India.
Ann Neurosci. 2022 Jan;29(1):32-52. doi: 10.1177/09727531211070541. Epub 2022 Mar 3.
Sympathetic innervation of lymphoid organs, and the presence of 17β-estradiol (estrogen or E2) and adrenergic receptors (ARs) on lymphocytes, suggests that sympathetic stimulation and hormonal activation may influence immune functions.
Modeling and simulating these pathways may help to understand the dynamics of neuroendocrine-immune modulation at the cellular and molecular levels.
Dose- and receptor-dependent effects of E2 and AR subtype-specific agonists were established in vitro on lymphocytes from young male Sprague-Dawley rats and were modeled in silico using the MATLAB Simbiology toolbox. Kinetic principles were assigned to define receptor-ligand dynamics, and concentration/time plots were obtained using Ode15s solvers at different time intervals for key regulatory molecules. Comparisons were drawn between in silico and in vitro data for validating the constructed model with sensitivity analysis of key regulatory molecules to assess their individual impacts on the dynamics of the system. Finally, docking studies were conducted with key ligands E2 and norepinephrine (NE) to understand the mechanistic principles underlying their interactions.
Adrenergic activation triggered proapoptotic signals, while E2 enhanced survival signals, showing opposing effects as observed in vitro. Treatment of lymphocytes with E2 shows a 10-fold increase in survival signals in a dose-dependent manner. Cyclic adenosine monophosphate (cAMP) activation is crucial for the activation of survival signals through extracellular signal-regulated kinase (p-ERK) and cAMP responsive element binding (p-CREB) protein. Docking studies showed the direct inhibition of ERK by NE and β2-AR by E2 explaining how estrogen signaling overrides NE-mediated immunosuppression in vitro.
The cross-talk between E2 and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype and coactivation-dependent manner in health and disease.
淋巴器官的交感神经支配，以及淋巴细胞上存在17β-雌二醇（雌激素或E2）和肾上腺素能受体（ARs），表明交感神经刺激和激素激活可能影响免疫功能。
对这些途径进行建模和模拟可能有助于在细胞和分子水平上理解神经内分泌-免疫调节的动态过程。
在体外建立了E2和AR亚型特异性激动剂对年轻雄性Sprague-Dawley大鼠淋巴细胞的剂量和受体依赖性效应，并使用MATLAB Simbiology工具箱进行了计算机模拟。分配动力学原理来定义受体-配体动态，并使用Ode15s求解器在不同时间间隔获取关键调节分子的浓度/时间图。对计算机模拟数据和体外数据进行比较，以通过对关键调节分子的敏感性分析来验证构建的模型，从而评估它们对系统动态的个体影响。最后，对关键配体E2和去甲肾上腺素（NE）进行对接研究，以了解它们相互作用的机制原理。
肾上腺素能激活触发促凋亡信号，而E2增强存活信号，呈现出与体外观察到的相反作用。用E2处理淋巴细胞可使存活信号以剂量依赖性方式增加10倍。环磷酸腺苷（cAMP）激活对于通过细胞外信号调节激酶（p-ERK）和cAMP反应元件结合（p-CREB）蛋白激活存活信号至关重要。对接研究表明NE直接抑制ERK，E2直接抑制β2-AR，这解释了雌激素信号如何在体外超越NE介导的免疫抑制。
E2和肾上腺素能信号通路之间的相互作用以受体亚型和共激活依赖性方式决定了健康和疾病状态下淋巴细胞的功能。
