Immune system activation and cognitive impairment in arterial hypertension

Abstract

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.

Keywords: arterial hypertension; cerebral small vessel disease; cognitive impairment; cytokines; immune system.

Graphical abstract

Figure 1.

Temporal framework and interactions at neurovascular-immune interfaces in the pathogenesis of arterial hypertension. The figure illustrates interactions of systemic inflammatory responses in arterial hypertension at neurovascular-immune interfaces with the following temporal framework: ① peripheral and meningeal immune system activation; ② induction of peripheral and meningeal immune system effector mechanisms; ③ which bridge the interaction between immune system, neurovascular unit, and glial inflammation, to ④ act on brain perfusion, (perivascular) clearance of toxic metabolites and synaptic and neuronal dysfunction, which underlie cognitive impairment. A: prohypertensive triggers comprise chronic activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), and increased secretion of catecholamines. B: these stimuli promote local inflammation and mechanical stress and lead to an activation of the immune system with recruitment of immune cells into the systemic circulation and a shift toward proinflammatory immunological regulators [cytokines, damage-associated molecular patterns (DAMPs)]. C–F: cellular and molecular changes of cerebral (micro)vessels in arterial hypertension, their interaction with immune cells and immunological regulators, and consequences for microglia and synapses/neurons. C: overview of the cranial/meningeal layers and brain vasculature. D: resident meningeal T helper cells (T_H17 cells) and γδ T cells secrete their main effector cytokine interleukin 17 (IL-17) into the cerebrospinal fluid (CSF) circulation, from where it reaches the perivascular space (PVS) of pial and penetrating arterioles. E: penetrating arteriole within the PVS: blood-derived immune regulators induce 1) endothelial IL-17/IL-17RA signaling, which inhibits endothelial nitric oxide (NO) synthase and 2) Ang-II/AT1R/NOX2 signaling in perivascular macrophages (PVM) producing reactive oxygen species (ROS). Both NO synthase inhibition and ROS impair endothelial vasodilation during neuronal activity, that is, neurovascular coupling. Neurovascular dysfunction can be rescued by IL-10 derived from regulatory T cells (T_reg cells). F: the blood-brain barrier (BBB): in response to arterial hypertension, BBB integrity is impaired due to endothelial downregulation of tight junction gene expression (occludin, OCLN; claudin-5, CLDN5) and pericyte injury allowing peripheral preactivated immune cells to immigrate and secrete proinflammatory cytokines. Gene expression of adhesion molecules [e.g., vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1)], chemokine secretion [e.g., CC-chemokin-ligand-2 (CCL2)], and presentation of brain-derived antigens by vascular cells activate CD8⁺ T cells, which can disturb BBB integrity. Microglia are activated and recruited to the vasculature and are able to phagocytose adjacent synapses. Created with BioRender.com. Ang-II, angiotensin II; AT1R, angiotensin II receptor type 1; BM, basement membrane; C1q, complement component 1q; EC, endothelial cell; IFN-γ, interferon γ; NOX2, NADPH oxidase 2; NK cells, natural killer cells; PDGFRβ, platelet-derived growth factor receptor β; SMC, smooth muscle cell; TNF, tumor necrosis factor.