The body’s first defense against invading pathogens or tissue injury is the innate immune system. Since excessive immune responses can be damaging, anti-inflammatory mechanisms function to control the pro-inflammatory response and prevent injury. The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response. Knowledge concerning innervation of the immune system offers a unique opportunity to explore previously unrecognized techniques to treat disease. It also enables consideration of the neurological basis of complementary and alternative medical therapies, such as meditation and acupuncture. This evolving area of research has implications for the pathogenesis of chronic inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes, and other conditions of excessive cytokine release.

Introduction:

Inflammation, defined as the development of pain, swelling, erythema, and warmth in response to an injury or infection, plays an important role in warding off invasion.¹ The immune system is the first line of defense against invading pathogens and proper functioning of this system is essential for survival.² A central feature of the immune response is the production and release of cytokines: proteins produced by immune cells to orchestrate inflammation. Invasion or injury activates a discrete, localized inflammatory response with release of cytokines including tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, high mobility group B1 (HMGB1), among others, that produce a precise, and tightly controlled response.^3,4 In the vast majority of cases, the innate immune system successfully thwarts pathogenic threats and restores homeostasis.³ Nonetheless, in some cases, the inflammatory response can become excessive or persistent, and mediate dysfunction and damage to normal tissue. Cytokine overproduction has been implicated in the pathogenesis of rheumatoid arthritis, Crohn’s disease/inflammatory bowel disease, atherosclerosis, type 2 diabetes, Alzheimer’s disease, multiple sclerosis, endotoxemia, and severe sepsis.^5,6

It has recently become known that the immune system can be significantly regulated by the vagus nerve.^1,2,7 Stimulation of this nerve releases acetylcholine which inhibits the release of pro-inflammatory cytokines by macrophages and other cytokine-producing cells to dampen inflammation. Elucidation of the neuroanatomy of this pathway has enabled investigation into drugs, therapeutic techniques such as electrical stimulation, and even complementary and alternative medical therapies to activate the pathway to decrease inflammation. Herein, we discuss the role of cytokines in the immune response, describe the inflammatory reflex and the cholinergic anti-inflammatory pathway, consider previous clinical trial results in the context of the inflammatory reflex, and present the potential relationship between the inflammatory reflex and the field of complementary and alternative medicine….

Acupuncture

In a study by Ouyang et al.⁴³ performed at the University of Texas, electroacupuncture (a modified form of acupuncture) was found to significantly increase vagus nerve activity as compared to baseline levels measured by spectral analysis of heart rate variability in female hound dogs. Electrical acupuncture has also been evaluated in healthy human subjects. Hsu et al.⁴⁴ studied the effect of electrical acupuncture on a variety of biological responses, including heart rate variability. This study included 10 healthy subjects who underwent electrical acupuncture on acupoint BL15—the bladder meridian. Both the normalized high frequency power component of heart rate variability (determined via spectral analysis of the electrocardiogram) and the normalized low frequency power components were significantly increased and decreased, respectively (P < 0.05).

In a related study, heart rate variability in 39 human subjects receiving acupuncture at the Neiguan (P6) point was compared to 38 subjects receiving sham acupuncture, and 34 subjects receiving no acupuncture.⁴⁵ Results revealed that normalized high-frequency power (used as the index of vagal modulation) after acupuncture increased significantly in the Neiguan group, but not in the sham acupuncture or no acupuncture groups. The RR interval (the interval between R waves in the electrocardiogram) was significantly increased in both acupuncture groups, but was not significantly altered in the group not receiving acupuncture. The authors concluded that acupuncture can increase vagus nerve activity. These results were confirmed in a subsequent study reported by Sakai and colleagues who studied the relationship between acupuncture manipulation, and sympathetic and parasympathetic autonomic function.⁴⁶ They found that acupuncture manipulation resulted in significant decreases in heart rate, a significant decrease in the low frequency components of heart rate variability, and a significant positive correlation between the high frequency component of heart rate variability and the number of acupuncture sensations. These and other studies have been interpreted to suggest that acupuncture may enhance vagus nerve activity…

Not only have acupuncture and meditation been advocated for the treatment of a myriad of inflammatory conditions, but behavioral modification, hypnosis, biofeedback, and cognitive and relaxation therapies have also been demonstrated to stimulate vagus nerve activity.^50–56 This research lays a solid foundation for future studies to determine whether these therapies are capable of activating the cholinergic inflammatory pathway. Such clinical trials may be considered for inflammatory conditions including diabetes, artherosclerosis, and arthritis, among others as indicated in Table 1.