Immune mechanisms in the pathophysiology of hypertension

Abstract

Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.

Figure 1:

Multiple hypertensive stimuli activate innate immune cells to promote inflammation leading to blood pressure elevations and end-organ damage. Innate immune cells, including monocytes, macrophages, dendritic cells (DCs), and neutrophils, are the first responders of the immune system and provide rapid, non-specific responses to tissue damage. With initial blood pressure elevations, factors such as increased endothelial cell stretch, high sodium concentrations, sympathetic nervous system (SNS) activation, and angiotensin II promote innate immune cell activation. As a result, monocyte/macrophages and DCs exhibit increased reactive oxygen species (ROS), isolevuglandin (IsoLG) adduct formation, and release of inflammatory cytokines that damage the surrounding tissue. Macrophages have diverse roles in hypertension. Renal macrophages have been found to promote juxtaglomerular (JG) production of renin. In response to osmotic stress, dermal macrophages secrete VEGF-C, promoting lymphangiogenesis. In DCs, IsoLG adducts can form neoantigens in association with increased surface expression of co-stimulatory molecules CD80 and CD86, suggesting an augmented ability to prime the adaptive immune response. Potential roles for neutrophils and mast cells in hypertension are less well defined. Neutrophils isolated from hypertensive patients display elevated superoxide anion release and increased neutrophil extracellular trap formation (NETosis). NETs have also been observed at sites of hypertensive end-organ damage in rodent models of hypertension. Elevated immunoglobulin E (IgE) in hypertension can also activate mast cells leading to enhanced secretion of interleukin-6 (IL-6).

Figure 2:. Multiple stimuli including innate immune cells activate T cells to promote hypertension development and related end-organ damage.

Increases in a variety of factors such as angiotensin II (Ang II), sympathetic outflow, reactive oxygen species (ROS), and interstitial sodium lead to immune cell activation in hypertension. This includes activation of adaptive immune cells, either directly or indirectly through antigen presenting cells (APCs). Cells of the adaptive immune system secrete factors including cytokines that promote hypertension and its associated end organ damage. CD8⁺ T cells primarily secrete interferon gamma (IFNγ) while CD4⁺ T cell subsets secrete characteristic cytokines including IFNγ by Th1 cells, interleukin-17A (IL-17A) by Th17 cells, and interleukin-21 (IL-21) by T follicular helper (Tfh) cells. These cytokines promote vascular dysfunction and remodeling and impair renal natriuretic function leading to blood pressure elevations and end organ damage in hypertension. In the vasculature, these cytokines inhibit nitric oxide production in endothelial cells, stimulates collagen synthesis by adventitial cells and promotes hypertrophic remodeling of mesenteric arteries by stimulating vascular smooth muscle cells (VSMC). In the kidney, the cytokines promote renal injury and alter sodium transporters. Tregs produce cytokines such as interleukin-10 (IL-10) and function to promote peripheral tolerance and limit hypertension development. IL-21 augments T cell production of IL-17A and IFNγ and limits Treg function, skewing the Th17/Treg axis towards a pro-inflammatory phenotype. Together, IL-17A, IFNγ, and IL-21 promote blood pressure elevation and end organ damage observed in hypertension. Gamma delta (γδ) T cells, and potentially innate lymphoid cells as well (ILCs), can also release cytokines such as IFNγ and IL-17A to enhance hypertension development.

Figure 3:. Immune cells play a central role in driving blood pressure elevations and end-organ damage that feeds forward to promote further increases in blood pressure.

Dysfunction of a variety of organs including the central nervous system (CNS), kidneys, vasculature, and heart leads to blood pressure elevations in hypertension. In addition, activation of immune cells can promote blood pressure elevations, at least in part through infiltration and damage of these hypertension-related organs. Blood pressure elevations in hypertension also directly promotes end-organ damage in the kidneys, heart, and vasculature leading to further immune cell infiltration and activation in a vicious cycle. Together, these processes suggest a central role for immune cells in the pathogenesis of hypertension that may be amenable to therapeutic targeting.