Vascular inflammatory cells in hypertension

Abstract

Hypertension is a common disorder with uncertain etiology. In the last several years, it has become evident that components of both the innate and adaptive immune system play an essential role in hypertension. Macrophages and T cells accumulate in the perivascular fat, the heart and the kidney of hypertensive patients, and in animals with experimental hypertension. Various immunosuppressive agents lower blood pressure and prevent end-organ damage. Mice lacking lymphocytes are protected against hypertension, and adoptive transfer of T cells, but not B cells in the animals restores their blood pressure response to stimuli such as angiotensin II or high salt. Recent studies have shown that mice lacking macrophages have blunted hypertension in response to angiotensin II and that genetic deletion of macrophages markedly reduces experimental hypertension. Dendritic cells have also been implicated in this disease. Many hypertensive stimuli have triggering effects on the central nervous system and signals arising from the circumventricular organ seem to promote inflammation. Studies have suggested that central signals activate macrophages and T cells, which home to the kidney and vasculature and release cytokines, including IL-6 and IL-17, which in turn cause renal and vascular dysfunction and lead to blood pressure elevation. These recent discoveries provide a new understanding of hypertension and provide novel therapeutic opportunities for treatment of this serious disease.

Keywords: T cells; blood pressure; dendritic cells; interleukin 17; interleukin 6; macrophages; superoxide; sympathetic nerves.

Figure 1

Proposed paradigm for inflammation and immune cell activation in hypertension. Stimuli including angiotensin II, salt, and chronic stress act on the central nervous system and increase sympathetic outflow. The circumventricular organs (CVO), including the subfornical organ (SFO), the medium preoptic eminence (MPO, orange structure) organum vasculosum lateral terminalis (OVLT, yellow structure), and the area postrema (AP) have a poorly formed blood–brain barrier and are responsive to circulating angiotensin II and sodium. These stimuli increase ROS production in the CVO, which provide input into hypothalamic centers including the paraventricular nucleus (PVN). Microglial cells are activated in this process, and increase input into brainstem centers including the ventral lateral medulla (VLM) and the nucleus tractus solitarius (NTS). These increase sympathetic outflow, which causes a modest elevation in blood pressure to levels compatible with pre-hypertension. Sympathetic stimulation also increases renal production of IL-6 and acts on T cell adrenergic receptors to modify their polarization. The elevations of pressure, direct actions and angiotensin II and catecholamines activate ROS production in the kidney and vasculature, increasing chemokine production and adhesion molecule expression. We propose that neoantigens (nAg) are formed from endogenous proteins in the kidney and vasculature, which are presented by dendritic cells to T cells. Activated T cells interact with monocyte/macrophages, promoting macrophage transformation and these leukocytes accumulate in the kidney. IL-6 and TGFβ, produced in these organs, help direct T cell IL-17 production. IL-17 and other cytokines produced by these cells promote ROS production in the vascular smooth muscle and kidney, leading to vasoconstriction, sodium retention, and ultimately severe hypertension.