ABSTRACT
A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.
Subject(s)
Cerebrovascular Disorders/chemically induced , Cognition Disorders/chemically induced , Intestine, Small/pathology , Sodium Chloride, Dietary/toxicity , Th17 Cells/drug effects , Acetylcholine/pharmacology , Amides/pharmacology , Animals , Antihypertensive Agents/pharmacology , Cell Differentiation/drug effects , Cell Polarity/drug effects , Cerebrovascular Circulation/drug effects , Cerebrovascular Disorders/drug therapy , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Interleukin-17/administration & dosage , Interleukin-17/blood , Interleukin-17/genetics , Interleukin-17/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurovascular Coupling/drug effects , Phosphorylation/drug effects , Pyridines/pharmacologyABSTRACT
Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.
