Elucidating molecular pathways regulating neuroimmune communication is critical for therapeutic interventions in conditions characterized by overactive immune responses and dysfunctional autonomic nervous system. We generated a bone marrow-specific adrenergic beta 1 and beta 2 knockout mouse chimera (AdrB1.B2 KO) to determine how sympathetic drive to the bone affects transcripts and miRNAs in the hypothalamic paraventricular nucleus (PVN). This model has previously exhibited a dampened systemic immune response and decreased blood pressure compared with control animals. Reduced sympathetic responsiveness of the bone marrow hematopoietic cells of AdrB1.B2 KO chimera led to suppression of transcriptional networks that included leukocyte cell adhesion and migration and T cell-activation and recruitment. Transcriptome responses related to IL-17a signaling and the renin-angiotensin system were also suppressed in the PVN. Based on the transcriptome response, we next computationally predicted miRNAs in the PVN that may underscore the reduced sympathetic responsiveness of the bone marrow cells. These included miR-27b-3p, miR-150, miR-223-3p, and miR-326. Using real-time PCR, we measured a downregulation in the expression of miR-150-5p, miR-205-5p, miR-223-3p, miR-375-5p, miR-499a-5p, miR-27b-3p, let-7a-5p, and miR-21a-5p in the PVN of AdrB1.B2 KO chimera, confirming computational predictions that these miRNAs are associated with reduced neuro-immune responses and the loss of sympathetic responsiveness in the bone marrow. Intriguingly, directional responses of the miRNA corresponded to mRNAs, suggesting complex temporal or circuit-dependent posttranscriptional control of gene expression in the PVN. This study identifies molecular pathways involved in neural-immune interactions that may act as targets of therapeutic intervention for a dysfunctional autonomic nervous system.

中文翻译：

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小鼠骨髓β-肾上腺素能受体的遗传消融调节脑室旁核中神经炎症的miRNA-转录组网络。

阐明调节神经免疫通讯的分子途径对于以免疫反应过度活跃和自主神经系统功能异常为特征的治疗干预至关重要。我们生成了骨髓特异性肾上腺素β1和β2基因敲除小鼠嵌合体（AdrB1.B2 KO），以确定对骨骼的交感神经驱动如何影响下丘脑室旁核（PVN）中的转录本和miRNA。与对照动物相比，该模型先前表现出减弱的全身免疫反应和降低的血压。AdrB1.B2 KO嵌合体骨髓造血细胞的交感反应性降低导致转录网络受到抑制，包括白细胞粘附和迁移以及T细胞活化和募集。在PVN中，与IL-17a信号转导和肾素-血管紧张素系统相关的转录组反应也被抑制。基于转录组反应，我们接下来在计算上预测PVN中的miRNA，这可能强调了骨髓细胞交感反应的降低。这些包括miR-27b-3p，miR-150，miR-223-3p和miR-326。使用实时PCR，我们测量了miR-150-5p，miR-205-5p，miR-223-3p，miR-375-5p，miR-499a-5p，miR-27b-3p， let-7a-5p和miR-21a-5p位于AdrB1.B2 KO嵌合体的PVN中，证实了计算预测，即这些miRNA与降低的神经免疫反应和骨髓中交感反应性丧失有关。有趣的是，miRNA的方向性反应对应于mRNA，提示PVN中基因表达的复杂的时间或电路依赖性转录后控制。这项研究确定了参与神经-免疫相互作用的分子途径，这些途径可能是功能障碍的自主神经系统的治疗干预目标。