Addressing the relationship between sympathetic activity and inflammation

In this issue of the Journal, Maritta K. Pöyhönen-Alho and coworkers present an intriguing study on the effects of differential antihypertensive medication (central-sympatholytic agent versus β-blocker) on insulin sensitivity and markers of inflammation in hypertensive overweight postmenopausal women [1]. A total of 87 women not taking any medication including hormone-replacement therapy were enrolled into the study. They were randomized to antihypertensive treatment with either atenolol 50 mg per day or moxonidine 0,3 mg twice daily. The authors applied assays for C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNFα), TNFα-RII and adiponectin and measured insulin sensitivity with an oral glucose tolerance test and calculation of the insulin-sensitivity index. The authors observed an increase in TNFα in the atenolol group as opposed to a decrease in TNFα in the moxonidine group. Adiponectine decreased in the atenolol-treated women and did not change significantly in women receiving moxonidine. The other parameters did not change with either treatment. Thus, the authors were able to show that a central sympatholytic agent reduces the level of a proinflammatory cytokine without affecting adiponectin levels in hypertensive overweight postmenopausal women. This study has intriguing findings as it relates pharmacological-central blockade of the sympathetic nervous system to a reduction in inflammatory markers. Peripheral β blockade did not have these beneficial effects. The effects of moxonidine were observed in a population of hypertensive overweight postmenopausal women – thus a population likely to have increased sympathetic tone and increased markers of inflammation [2,3]. The effects of moxonidine were not attributable to a more pronounced decrease in blood pressure with moxonidine. There is profound evidence that central sympathetic activation is related to insulin resistance and vice versa [2,4], reduction of sympathetic activity – at least in the context of overweight insulin-resistant subjects – is related to improved insulin sensitivity [5]. The mechanisms responsible for the interplay between central sympathetic outflow and insulin resistance are not completely understood. Important factors are certainly impaired skeletal muscle vasodilatation and impaired metabolic effects induced by central sympathetic overactivity [2,4,6]. Biological markers of inflammation are related to adverse cardiovascular events, most data exist on CRP [7,8]. CRP is strongly related to atherosclerosis, and TNFα is a potent proatherogenic adipokine. TNFα in turn is inhibited by adiponectin, a cytokine with antiatherosclerotic properties released from adipose tissue. Adiponectin release is modulated by the sympathetic nervous system. Sympathetic activation has been reported to reduce adiponectin release, whereas central-sympathetic blockade may increase adiponectin levels [9,10]. Taken together, sympathetic overactivity, adipokines and markers of inflammation are under mutual influence and related to insulin resistance and the metabolic syndrome. These are important regulators of cardiovascular risk. Therefore, it is very intriguing to evaluate the effects of central sympathetic blockade on parameters of inflammation in the context of overweight hypertensive subjects, as done by Pöyhönen-Alho et al. in this issue of the Journal [1]. However, the potential implication for the interaction between the sympathetic nervous system and inflammation is far beyond their role in atherosclerosis. Importantly, sympathetic nerve fibers as well as cholinergic vagal fibers innervate organs of the immune system such as lymph nodes and the spleen [11]. Indeed, there is a substantial amount of evidence linking sympathetic activation to inflammation. Ganta et al.[12] were able to show that sympathetic activation induced by intracerebroventricular administration causes increased splenic-cytokine expression. As outlined by Ader et al.[13], the sympathetic nervous system innervates organs of the immune system, and there are bidirectional pathways of communication between both [14]. Sympathetic activation may enhance immune responses but may also decrease the immune competence. As reviewed by Nance and Sanders [11], sympathetic activation inhibits the activity of cells associated with the innate-immune system, whereas it may influence in both ways the activity of cells associated with the acquired, that is, adaptive-immune system. Innate-immune cells express both α and β-adrenergic receptors, whereas T and B-lymphocytes of most species express beta2 adrenergic receptors solely. Via these adrenergic receptors, norepinephrine can regulate the level of immune cell activity by modifying the level of cellular activity. This often involves alterations of gene expression for cytokines and antibodies. On the contrary, cholinergic activation has strong anti-inflammatory effects, partly via TNFα inhibition. In models of sepsis, sympathetic activation and cholinergic inhibition may cause exaggerated immune responses contributing to a detrimental clinical course of sepsis [14]. Moreover, the autonomic-nervous system is involved in endogenous cancer defense and autoimmune disease such as rheumatoid arthritis, juvenile diabetes or fibromyalgia [15]. Moreover, the autonomic-nervous system may be involved in changes in the immune system due to psychosocial stress [16,17]. It has to be emphasized that there is a bidirectional interaction between the immune system and the sympathetic nervous system. In a recent review by Czura and Tracy [15], the authors present evidence that the central-nervous system receives input from the immune system via both humoral and neural pathways. Interleukins and TNF may, for example, penetrate into the brain and regulate the activity of the autonomic-nervous system. In addition, the central-nervous system is informed about the status of inflammation via neural signals involving afferent-sympathetic fibers. Therapeutic interventions modifying the interplay between the autonomic-nervous system and inflammation appear to be an evolving field of research. Electric-vagal nerve stimulation or the application of cholinergic-receptor agonists such as, nicotine is example of procedures currently being evaluated in animal studies [15]. As outlined below, a systematic evaluation of the effects central-sympathetic inhibition on the immune system is desirable. With respect to the study population, the immunomodulating role of estrogens has to be taken into account [18]. Estrogens have complex anti-inflammatory, immunosupportive and also pro-inflammatory effects, particularly in some autoimmune diseases. Since all women studied by Pöyhönen-Alho et al. were postmenopausal, estrogens are unlikely to interfere with the observed effects of moxonidine. Pöyhönen-Alho and coworkers showed that central sympathetic blockade has some anti-inflammatory effects in hypertensive overweight menopausal women. However, the effects were only mild and somewhat incomplete. Most of the studied cytokines did not respond to either treatment and insulin sensitivity did not change significantly in either group. This may be due to the relatively short duration of the study and the relatively low dose of moxonidine applied. Given the complex immunomodulating effects of estrogen, it is unclear whether central-sympathetic blockade may influence markers of inflammation in premenopausal women. Also the effects in men need to be studied. Although the adverse role of sympathetic overactivity on cardiovascular outcome has been clearly shown in patients with heart failure [19] and end-stage renal disease [20] and there is also some evidence in patients with hypertension [21], we are still lacking evidence that pharmacological blockade of central sympathetic outflow improves cardiovascular prognosis. Thus the prognostic significance of the mild anti-inflammatory properties of moxonidine as observed by Pöyhönen-Alho et al. remains to be established. However, the potential implications of the interrelation between the sympathetic nervous system and the immune system are tremendous. These comprise the progression of atherosclerosis, the immune response against microbiological agents, for example, in sepsis, the modulation of autoimmune disease and finally the modulation of cancer progression. Further studies are warranted to elucidate pathophysiology and potential therapeutic interventions.