Stefanie Schreiber, Philipp Arndt, Lorena Morton, Alejandra P Garza, Patrick Müller, Katja Neumann, Hendrik Mattern, Marc Dörner, Jose Bernal, Stefan Vielhaber, Sven G Meuth, Ildiko R Dunay, Alexander Dityatev, Solveig Henneicke
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引用次数: 0
摘要
慢性动脉高血压会破坏脑微血管的完整性,使老年痴呆症的风险增加一倍。尽管进行了充分的降压治疗,但仍有相当一部分人单靠降压并不能保持认知健康。越来越多的证据凸显了炎症机制在高血压发病机制中的作用。在这篇综述中,我们介绍了一个时间框架,以探讨早期免疫系统激活和神经血管-免疫界面的相互作用如何为认知障碍铺平道路。总体范式表明,促高血压刺激会诱发机械应激和全身炎症反应,从而使外周和脑膜免疫效应机制转向促炎症状态。大脑中的神经血管-免疫界面包括功能失调的血脑屏障,由外周免疫细胞穿过;血管周围空间,其中巨噬细胞对脑脊液和血液衍生的免疫调节剂做出反应;以及脑膜免疫库,尤其是 T 细胞。这些界面上的免疫反应是外周和神经血管单元炎症的桥梁,直接导致脑灌注、有毒代谢物清除和突触功能受损。我们建议,生物流体中的深度免疫分型与先进的神经影像学相结合,可帮助转化确定动脉高血压特有的连续免疫和大脑内型。这将填补有关免疫系统激活如何以及何时转变为神经血管功能障碍和认知障碍的知识空白。未来,针对特定的免疫机制可以在临床症状出现之前预防和阻止高血压疾病的发展,从而满足对认知健康的主要威胁之一的新干预措施的需求。
Immune system activation and cognitive impairment in arterial hypertension.
Chronic arterial hypertension disrupts the integrity of the cerebral microvasculature, doubling the risk of age-related dementia. Despite sufficient antihypertensive therapy in still a significant proportion of individuals blood pressure lowering alone does not preserve cognitive health. Accumulating evidence highlights the role of inflammatory mechanisms in the pathogenesis of hypertension. In this review, we introduce a temporal framework to explore how early immune system activation and interactions at neurovascular-immune interfaces pave the way to cognitive impairment. The overall paradigm suggests that prohypertensive stimuli induce mechanical stress and systemic inflammatory responses that shift peripheral and meningeal immune effector mechanisms toward a proinflammatory state. Neurovascular-immune interfaces in the brain include a dysfunctional blood-brain barrier, crossed by peripheral immune cells; the perivascular space, in which macrophages respond to cerebrospinal fluid- and blood-derived immune regulators; and the meningeal immune reservoir, particularly T cells. Immune responses at these interfaces bridge peripheral and neurovascular unit inflammation, directly contributing to impaired brain perfusion, clearance of toxic metabolites, and synaptic function. We propose that deep immunophenotyping in biofluids together with advanced neuroimaging could aid in the translational determination of sequential immune and brain endotypes specific to arterial hypertension. This could close knowledge gaps on how and when immune system activation transits into neurovascular dysfunction and cognitive impairment. In the future, targeting specific immune mechanisms could prevent and halt hypertension disease progression before clinical symptoms arise, addressing the need for new interventions against one of the leading threats to cognitive health.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.