Vagus Nerve Stimulation and Regulation of Inflammation

Therapeutic Challenges in Inflammatory Disease

Inflammation is essential for antimicrobial defense and tissue healing but it must be proportional to the injury or threat and very carefully regulated to restore and maintain homeostasis and health. Excessive and nonresolving inflammation disrupts homeostasis and causes inflammatory diseases. Immune system dysregulation underlies septic shock, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, atherosclerosis, certain cancers, and a range of other diseases. Consequently, world-wide, nonresolving inflammation causes significant morbidity and mortality ( ).

The course of many diseases can be significantly improved by therapeutic modulation of inflammation. Steroidal and nonsteroidal antiinflammatory drugs, small molecule compounds, and specific anticytokine therapies are widely used in current clinical practice. However, these treatments may cause serious side effects and yet fail to provide satisfactory relief for a significant group of patients. Development of effective therapies with limited side effects to regulate specific inflammatory processes has proven challenging, and paradigm-shifting innovations are needed ( ).

Neural reflex circuits are key regulators of organ function and homeostasis. For example, heart rate, blood pressure, and body temperature are closely monitored by the nervous system and regulated by neural signals. The brain and the nervous system play key roles in maintaining physical balance and homeostasis under various conditions and challenges. Developments in bioelectronic medicine, defined as the convergence of molecular medicine, neuroscience, engineering, and computing, have revealed that neural reflexes also regulate inflammation, cytokine release, and a range of immune system functions. These new discoveries offer a conceptually new approach to use medical devices that modulate nerve activity to regulate inflammation and treat inflammatory disease. It is now conceivable to use electricity instead of drugs to target therapeutic molecular mechanisms through either stimulation or inhibition of peripheral nerves.

The Nervous System is an Integral Part of the Immune System

About 2000 years ago, described the hallmarks of inflammation, which include local redness, swelling, heat, and pain (Original before 47 CE.). A component of pain in peripheral inflammation is detected through increased signals in sensory nerve fibers. The signals travel to the brain and constitute one of the routes that convey information on the intensity and localization of the insult, and alert the organism to the trigger. Inflammation often elicits a “sickness syndrome,” which includes fatigue, loss of appetite, decreased social interactions, and increased sleep. These behavioral changes, in response to immune system activation, are orchestrated by the central nervous system (CNS) through a network of neural signals ( ). Hence, interactions between the immune system and the nervous system influence organism behavior. However, the detailed physiology of these interactions and the underlying molecular mechanisms have long remained unexplored, and much remains to be discovered.

Interestingly, neural control of inflammation is an ancient component of animal physiology ( ). Caenorhabditis elegans ( C . elegans ) is a nematode equipped with a feeding system, gut, and a nervous system, but lacks skeletal elements and a circulatory system. It is one of the least complex animals with a nervous system. In this relatively simple organism, the innate immune response to bacterial invasion of nonneural cells is regulated by nerve signals ( ). Neural reflexes constitute an integral part of the immune system in higher vertebrates as well, and our understanding of the underlying molecular mechanisms has expanded significantly ( ).

Importantly, specific pain fibers detect and respond to inflammation and have the capacity to regulate local inflammatory responses. Sensory, or nociceptor, nerve fibers can directly detect bacterial invasion and play a direct role in inhibition of the local inflammation, elicited by microbial invasion ( ). In other experimental models of inflammatory disease, the interaction between immune cells, tissues, and sensory nerve fibers promote inflammation ( ). Certain sensory nerves can also release substances that promote local inflammation and plasma leakage in response to irritants such as capsaicin in a response often referred to as “neurogenic inflammation” ( ). Thus, depending on the specific interactions between neurons, leukocytes, and tissues, nociceptor neurons can promote or inhibit inflammation ( ).

The CNS plays a vital role in orchestrating the systemic inflammatory response. The CNS receives information on inflammation through “danger receptors,” including toll-like receptors and cytokine receptors that activate central and peripheral signaling pathways. For example, bacterial endotoxin activates the hypothalamic–pituitary–adrenal (HPA) axis. This activation increases levels of antiinflammatory steroids, which suppress release of proinflammatory cytokines ( ). Circuits in the sympathetic and parasympathetic nervous systems also regulate local and systemic inflammation and immune responses ( ). Blocking these pathways disrupts normal physiology: Subdiaphragmatic vagotomy abolishes the centrally mediated hyperthermia induced by intraperitoneal injection of interleukin 1β, illustrating that sensory neurons in the autonomic nervous system have the capacity to detect signs of inflammation ( ). Also, injection of interleukin 1β into the rat portal vein elicits afferent, vagus nerve activity and reflex, efferent signal activity in the splenic nerve ( ) and pathogen-associated molecular patterns, recognized by sensory vagus neurons, can elicit reflex neural activity in efferent pathways ( ). In addition, a range of centrally acting drugs, including activators of central muscarinic receptors, reduce the systemic inflammatory response in murine endotoxemia ( ; ) and the vagus nerve plays a key role in attenuation of both systemic and local inflammation in a range of experimental models ( ) and may also influence development of oral tolerance ( ). Thus, accumulating evidence shows that neural reflex circuits detect microbial invasion, tissue damage and signs of inflammation, and respond with local regulation of inflammation and immunity as part of a systemic adaptation to return the organism to homeostasis and health. The nervous system is functionally an integral part of the immune system.