Vagal tone and the inflammatory reflex

THE INFLAMMATORY REFLEX

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.⁵

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

The sympathetic system has both pro- and anti-inflammatory influences. The inflammatory response is a cascade of cytokines, such that it may begin with the release of TNF-alpha, leading to the production of IL-1 and IL-6. IL-6 has both pro- and anti-inflammatory properties and represents a negative feedback mechanism. Expression of IL-6 in the liver promotes the production of the acute-phase reactant C-reactive protein (CRP). Therefore, activation of the cholinergic receptor to induce acetylcholine release may be an early intervention to short-circuit this inflammatory cascade, a potential therapeutic strategy to blunt inflammatory-mediated disease.

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.⁶ Most previous studies in which the relationship between HRV and CRP (or other inflammatory markers) was assessed failed to control for sympathetic nervous system activity. In the total sample and in men, the parasympathetic effect on CRP was comparable with that of smoking; in women, the effect was 4 times larger and comparable with that of high body mass index. A negative association was again found between vagally mediated HRV and white blood cell count.

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.⁷ Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis. Meta-analyses have shown a prospective association between elevated plasma fibrinogen levels even in the normal range and an increased risk of coronary artery disease in different populations. We investigated the relationship between nighttime HRV, assessed by root mean square of successive R-R interval differences (RMSSD), and fibrinogen in 559 mostly male workers from southern Germany. Among all workers, there was a mean ± SEM increase of 0.41 ± 0.13 mg/dL fibrinogen for each ms decrease in nighttime RMSSD, even after controlling for established cardiovascular risk factors. The increase in men was 0.28 ± 0.13 mg/dL and, in women, 1.16 ± 0.41 mg/dL for each ms decrease in nighttime RMSSD. Such an autonomic mechanism might contribute to the atherosclerotic process and its thrombotic complications.

Vagal regulation of allostatic systems

Whereas the role of the autonomic nervous system, and the vagus nerve in particular, in the regulation of the cardiovascular system seems clear, the role of the vagus nerve in the regulation of other systems associated with allostasis is less evident. In addition to the regulation of inflammatory markers as discussed thus far, decreased vagal function and HRV have been associated with increased fasting glucose and glycated hemoglobin (HbA_1c) levels, and with increased overnight urinary cortisol.⁸ These factors have been associated with increased allostatic load and poor health. Thus, vagal activity seems to have an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems, including inflammation via the vagus nerve. The next section describes evidence for the prefrontal regulation of inflammation.

Prefrontal cortical activity and immune indices

Ohira et al used neuroimaging to explore the association between the brain and immune function.⁹ Their study examined the neural basis of the top-down modulation accompanying cognitive appraisal during a controllable or uncontrollable acute stressor. HR and blood pressure increased significantly during a mental arithmetic task and returned to baseline soon after termination of the task. HR increased to a greater extent in the controllable versus the uncontrollable condition; blood pressure was unaffected by controllability. Endocrine and immune indices were also affected by the acute stress task: the proportions of natural killer cells increased and helper T cells decreased acutely during the stressor.

Importantly, cerebral blood flow measurements demonstrated that the areas of the prefrontal cortex that we have found to be associated with HRV, including the medial prefrontal cortex and the insula, were also associated with immune indices (medial and lateral orbitofrontal cortices and insula), suggesting prefrontal or frontal modulation of immune responses possibly via the same vagal pathways.

VAGAL ACTIVITY AND CARDIOVASCULAR RISK FACTORS

The regulation of physiologic systems that are important for health and disease has been linked to vagal function and HRV. We have recently reviewed the literature on the relationship between vagal function and the risk for cardiovascular disease and stroke. The National Heart, Lung, and Blood Institute lists eight risk factors for heart disease and stroke.¹⁰ Six are considered modifiable. Of the six modifiable factors, three are associated with what could be called biologic factors: high blood pressure (hypertension), diabetes, and abnormal cholesterol; the other three could be considered lifestyle factors: tobacco use (smoking), physical inactivity (exercise), and overweight (obesity). Two factors, age and family history of early heart disease or stroke, are considered nonmodifiable. At least some data suggest that each of these risk factors is associated with decreased vagal function as indexed by HRV.¹¹

Interventions to modify HRV include exercise, ingestion of omega-3 fatty acids, stress reduction (eg, mediation), pharmacologic manipulations, and vagus nerve stimulation, suggesting that methods that increase vagus nerve activity might favorably modify an individual’s risk profile.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.