Department of Neuroscience, Wexner Medical Center, The Ohio State University, 43210, Columbus, OH, USA.
Institute for Behavioral Medicine Research, Wexner Medicine Center, The Ohio State University, 43210, Columbus, OH, USA.
Neuropsychopharmacology. 2022 Dec;47(13):2271-2282. doi: 10.1038/s41386-022-01434-x. Epub 2022 Sep 14.
Chronic stress may precipitate psychiatric disorders including anxiety. We reported that Repeated Social Defeat (RSD) in mice increased accumulation of inflammatory monocytes within the brain vasculature, which corresponded with increased interleukin (IL)-1 Receptor 1-mediated activation of endothelia, and augmented anxiety-like behavior. One unknown, however, is the role of immune-activated endothelia in regulating the physiological and behavioral responses to social stress. Thus, we sought to determine the RNA profile of activated endothelia and delineate the pathways by which these endothelia communicate within the brain to influence key responses to social stress. First, endothelial-specific RiboTag mice were exposed to RSD and brain endothelial mRNA profiles from the whole brain and prefrontal cortex were determined using RNAseq. RSD increased expression of cell adhesion molecules (Icam1), inflammatory genes (Lrg1, Lcn2, Ackr1, Il1r1), and cyclooxygenase-2 (Ptgs2/COX-2). In studies with IL-1R1 mice, there was clear dependence on IL-1R1 on endothelia-associated transcripts including Lrg1, Icam1, Lcn2. Moreover, prostaglandin (PG)E2 was increased in the brain after RSD and Ptgs2 was localized to endothelia, especially within the hypothalamus. Next, a selective COX-2 inhibitor, Celecoxib (CCB), was used with social stress. RSD increased PGE2 in the brain and this was abrogated by CCB. Moreover, CCB reduced RSD-induced Hypothalamic-Pituitary-Adrenal (HPA) axis activation with attenuation of hypothalamic paraventricular neuron activation, hypothalamic Crh expression, and corticosterone in circulation. Production, release, and accumulation of inflammatory monocytes after RSD was COX-2 independent. Nonetheless, CCB blocked anxiety-like behavior in response to RSD. Collectively, social stress stimulated specific endothelia RNA profiles associated with increased cell adhesion, IL-1 and prostaglandin signaling, HPA axis activation, and anxiety.
慢性应激可能会引发包括焦虑在内的精神疾病。我们曾报道过，在小鼠中反复的社交挫败（RSD）会增加血管内皮内炎症单核细胞的积累，这与白细胞介素（IL）-1 受体 1 介导的内皮激活增加以及焦虑样行为增加相对应。然而，一个未知的因素是免疫激活的内皮细胞在调节对社会压力的生理和行为反应中的作用。因此，我们试图确定激活的内皮细胞的 RNA 谱，并描绘这些内皮细胞在大脑内相互交流以影响对社会压力的关键反应的途径。首先，使用 RiboTag 小鼠使内皮细胞特异性暴露于 RSD，并使用 RNAseq 确定来自整个大脑和前额叶皮层的脑内皮细胞 mRNA 图谱。RSD 增加了细胞粘附分子（Icam1）、炎症基因（Lrg1、Lcn2、Ackr1、Il1r1）和环氧化酶-2（Ptgs2/COX-2）的表达。在 IL-1R1 小鼠的研究中，IL-1R1 对包括 Lrg1、Icam1 和 Lcn2 在内的内皮相关转录物的依赖性非常明显。此外，RSD 后大脑中的前列腺素（PG）E2 增加，Ptgs2 定位于内皮细胞，尤其是在下丘脑。接下来，使用选择性 COX-2 抑制剂 Celecoxib（CCB）与社交压力一起使用。RSD 增加了大脑中的 PGE2，而 CCB 则消除了这一作用。此外，CCB 减少了 RSD 诱导的下丘脑-垂体-肾上腺（HPA）轴激活，减弱了下丘脑室旁神经元的激活、下丘脑 CRH 表达和循环中的皮质酮。RSD 后炎症单核细胞的产生、释放和积累与 COX-2 无关。尽管如此，CCB 还是阻断了 RSD 引起的焦虑样行为。总的来说，社交压力刺激了与细胞粘附、IL-1 和前列腺素信号、HPA 轴激活和焦虑相关的特定内皮细胞 RNA 谱。
