Immune mechanisms of hypertension

Abstract

Hypertension affects 30% of adults and is the leading risk factor for heart attack and stroke. Traditionally, hypertension has been regarded as a disorder of two systems that are involved in the regulation of salt–water balance and cardiovascular function: the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS). However, current treatments that aim to limit the influence of the RAAS or SNS on blood pressure fail in ~40% of cases, which suggests that other mechanisms must be involved. This Review summarizes the clinical and experimental evidence supporting a contribution of immune mechanisms to the development of hypertension. In this context, we highlight the immune cell subsets that are postulated to either promote or protect against hypertension through modulation of cardiac output and/or peripheral vascular resistance. We conclude with an appraisal of knowledge gaps still to be addressed before immunomodulatory therapies might be applied to at least a subset of patients with hypertension.

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Fig. 1: Timeline of research linking immunity and hypertension.
Fig. 2: Pro-hypertensive actions of B cells.
Fig. 3: Immune and non-immune mechanisms of hypertension.

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Acknowledgements

G.R.D., A.V. and C.G.S. are supported by grants and/or fellowships from the National Health and Medical Research Council of Australia (APP1143674, APP1144243 and APP1079467). T.J.G. is supported by a European Research Council Consolidator Grant (726318) and the PLAQUEFIGHT/ERA CVD JTC2017 project.

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Nature Reviews Immunology thanks D. Carnevale, M. S. Madhur and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Grant R. Drummond.

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Glossary

Sympathetic nervous system

(SNS). The division of the autonomic nervous system that is involved in maintaining or increasing blood pressure through the release of catecholamines such as noradrenaline and adrenaline.

Renin–angiotensin–aldosterone system

(RAAS). A multifactorial hormone system involving the renin-induced generation of angiotensin II and subsequently aldosterone, which regulates blood pressure and fluid balance.

Hypothalamus

A small region of the brain that integrates central and peripheral inputs to modulate autonomic nerve function, including those circuits of the sympathetic nervous system that control blood pressure.

Rostral ventrolateral medulla

A brain region involved in basal and reflex control of blood pressure. It functions as a primary regulator of the sympathetic nervous system via catecholaminergic and glutaminergic projections to sympathetic preganglionic neurons.

Endothelial dysfunction

The decreased endothelial production and/or availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors.

Severe combined immunodeficient mice

(SCID mice). Mice genetically immunodeficient owing to impaired development of B cells and T cells.

Renal arteriolar rarefaction

A decreased density of arterioles within the kidneys.

Fcγ receptors

(FcγRs). Members of a superfamily of immunoglobulin receptors comprising several subtypes that bind to IgG with differing affinities to evoke a range of immune responses, including phagocytosis of opsonized microorganisms, induction of antibody-dependent cell-mediated cytotoxicity, cell activation and cytokine release.

Macrophage polarization

M1 and M2 macrophage polarization states are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Fcgr2b −/− mice

Mice lacking the Fcgr2b gene, which encodes a subtype of inhibitory Fcγ receptor (FcγR) that is expressed on B cells, myeloid dendritic cells and endothelial cells and has a role in immune tolerance.

Isolevuglandin-modified proteins

Modified proteins formed by the reaction of isolevuglandins with lysyl residues that may function as danger-associated molecular patterns or neoantigens.

Invariant natural killer T cells

(iNKT cells). A subset of natural killer T cells expressing an invariant T cell receptor α-chain. These cells respond rapidly to danger signals and pro-inflammatory cytokines and promote activation of T cells, B cells, dendritic cells and macrophages.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of immune cells of myeloid lineage, which markedly expand in pathological situations and inhibit the effector function of lymphocytes.

Pre-eclampsia

A disorder of pregnancy involving increased blood pressure.

Hyperuricaemia

Increased levels of uric acid in the blood.

Urolithiasis

Kidney stone disease.

Noradrenergic drive

The process of promoting activation of sympathetic nerves to release noradrenaline (norepinephrine).

Vagus–splenic nerve drive

The process of promoting activation of the left efferent branch of the vagus nerve to the noradrenergic splenic nerve.

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