Sympathetic-mediated activation versus suppression of the immune system: consequences for hypertension

Abstract

It is generally well-accepted that the immune system is a significant contributor in the pathogenesis of hypertension. Specifically, activated and pro-inflammatory T-lymphocytes located primarily in the vasculature and kidneys appear to have a causal role in exacerbating elevated blood pressure. It has been proposed that increased sympathetic nerve activity and noradrenaline outflow associated with hypertension may be primary contributors to the initial activation of the immune system early in the disease progression. However, it has been repeatedly demonstrated in many different human and experimental diseases that sympathoexcitation is immunosuppressive in nature. Moreover, human hypertensive patients have demonstrated increased susceptibility to secondary immune insults like infections. Thus, it is plausible, and perhaps even likely, that in diseases like hypertension, specific immune cells are activated by increased noradrenaline, while others are in fact suppressed. We propose a model in which this differential regulation is based upon activation status of the immune cell as well as the resident organ. With this, the concept of global immunosuppression is obfuscated as a viable target for hypertension treatment, and we put forth the concept of focused organ-specific immunotherapy as an alternative option.

Figure 1

Proposed model for the opposing effects of increased sympathetic drive on T‐lymphocytes in hypertension Numerous factors such as increased AngII, genetic predisposition, shear stress, or high salt have been shown to elicit damage to susceptible organs such as the vasculature and kidney, while additionally having direct effects on the central nervous system (CNS). This damage can lead to a localized inflammatory response in which T‐lymphocytes become activated and polarized producing cytokines such as IFNγ and IL‐17. It is believed that this inflammation is detected in the brain via afferent nerve pathways, further increases in circulating AngII, and pro‐inflammatory cytokines, which in turn triggers increased efferent sympathetic nerve activity and NA outflow. In sites where T‐lymphocytes are activated and polarized (i.e. vasculature and kidney), NA potentiates the inflammation, while NA has direct inhibitory effects on naive T‐lymphocytes localized to lymphoid organs such as the spleen or lymph nodes.