Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic?

Abstract

Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.

Keywords: T-lymphocytes; autoimmunity; cytokines; dendritic cells; hypertension; immunity; inflammation.

Figure 1:

Proposed Role of Immune Activation in Hypertension.

Figure 2:. The NLRP3 Inflammasome in Hypertension.

The NLRP3 inflammasome begins its activation through a priming step mediated by the transcription factor NF-κB, which upregulates inflammasome components NLRP3 and pro-IL-1β. Multiple endogenous vasoactive molecules including Endothelin-1, Aldosterone, Angiotensin II, and NaCl can serve as priming stimuli. A second activation step is needed to trigger the formation of the components into the NLRP3 inflammasome signaling complex. Once assembled, caspase-1 proteolytically cleaves pro-IL-1β into the released IL-1β. NLRP3 inflammasome activation has been shown to play a role in the induction of renal injury and vascular remodeling, ultimately leading to hypertension. (Illustration Credit: Ben Smith)

Figure 3:. Innate and adaptive immune cells that have been implicated in hypertension pathophysiology.

Cells of the innate and adaptive immune system secrete factors including reactive oxygen species (ROS), hydrogen peroxide (H₂O₂), and cytokines that promote or inhibit hypertension and hypertensive end-organ damage. The role of eosinophils and B cells, which secrete immunoglobulins such as IgG, is still unclear. (Illustration Credit: Ben Smith)

Figure 4:. Aldosterone-independent activation of ENaC in immune cells.

Extracellular Na⁺ activates the amiloride-inhibitable channel ENaC, which leads to influx in intracellular calcium via the sodium-calcium exchanger. This influx of Ca2+ activates protein kinase-C (PKC). PKC then phosphorylates p47phox leading to the assembly and activation of NADPH oxidase and subsequent production of superoxide and isoLG-adducted proteins. Increased intracellular sodium influx stimulates SGK1 mediates expression and assembly of ENaC in immune cells. Additionally, EETs inhibit ENaC channel activity in these cells. (Illustration Credit: Ben Smith)

Figure 5:. Risk factors contributing to inflammation and hypertension.

Risk factors including viral infections, high salt diet, genetics, and the microbiome lead to an inflammatory milieu that contributes to hypertension.