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The inflammatory reflex is a neural circuit that regulates the immune response to injury and invasion. All reflexes have an afferent and efferent arc. The Inflammatory reflex has a sensory afferent arc, which is activated by cytokines, and a motor or efferent arc, which transmits action potentials in the vagus nerve to suppress cytokine production. Increased signaling in the efferent arc inhibits inflammation and prevents organ damage.
It has also been shown that the brain can use this circuit not only to regulate the immune response but also to extend the immunological memory [1] [2]
The molecular basis of cytokine-inhibiting signals requires the neurotransmitter acetylcholine, and the Alpha-7 nicotinic receptor receptor expressed on cytokine-producing cells. [3] [4] The release of acetylcholine in spleen suppresses the production of TNF and other cytokines which causes damaging inflammation. [5] Signaling in the efferent arc of the inflammatory reflex, termed the "Cholinergic anti-inflammatory pathway," provides a regulatory check on the innate immune system response to invasion and injury. The action potentials that arise in the vagus nerve are transmitted to the spleen, where a subset of specialized T cells are activated to secrete acetylcholine. The net effect of the reflex is to prevent the damage caused by excessive cytokine production. [6]
Evidence from experimental disease models of arthritis, colitis, sepsis, hemorrhagic shock, and congestive heart failure indicate that electrical stimulation of the vagus nerve can prevent or reverse these diseases. [7] Some research suggests that it is possible to implant nerve stimulants to replace anti-inflammatory drugs that target cytokine activity (e.g. anti-TNF and anti-IL-1 antibodies). [8]
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that carries sensory fibers that create a pathway that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right vagus nerves—but they are typically referred to collectively as a single subsystem. The vagus is the longest nerve of the autonomic nervous system in the human body and comprises both sensory and motor fibers. The sensory fibers originate from neurons of the nodose ganglion, whereas the motor fibers come from neurons of the dorsal motor nucleus of the vagus and the nucleus ambiguus. The vagus was also historically called the pneumogastric nerve.
Cytokines are a broad and loose category of small proteins important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the nervous system that supplies internal organs, smooth muscle and glands. The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, its force of contraction, digestion, respiratory rate, pupillary response, urination, and sexual arousal. This system is the primary mechanism in control of the fight-or-flight response.
The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes considered an independent system.
The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system (ANS) and consists of a mesh-like system of neurons that governs the function of the gastrointestinal tract. It is capable of acting independently of the sympathetic and parasympathetic nervous systems, although it may be influenced by them. The ENS is nicknamed the "second brain". It is derived from neural crest cells.
Tumor necrosis factor is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
The pupillary light reflex (PLR) or photopupillary reflex is a reflex that controls the diameter of the pupil, in response to the intensity (luminance) of light that falls on the retinal ganglion cells of the retina in the back of the eye, thereby assisting in adaptation of vision to various levels of lightness/darkness. A greater intensity of light causes the pupil to constrict, whereas a lower intensity of light causes the pupil to dilate. Thus, the pupillary light reflex regulates the intensity of light entering the eye. Light shone into one eye will cause both pupils to constrict.
In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, is a series of purely sensory nuclei forming a vertical column of grey matter embedded in the medulla oblongata. Through the center of the SN runs the solitary tract, a white bundle of nerve fibers, including fibers from the facial, glossopharyngeal and vagus nerves, that innervate the SN. The SN projects to, among other regions, the reticular formation, parasympathetic preganglionic neurons, hypothalamus and thalamus, forming circuits that contribute to autonomic regulation. Cells along the length of the SN are arranged roughly in accordance with function; for instance, cells involved in taste are located in the rostral part, while those receiving information from cardio-respiratory and gastrointestinal processes are found in the caudal part.
The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.
Vagovagal reflex refers to gastrointestinal tract reflex circuits where afferent and efferent fibers of the vagus nerve coordinate responses to gut stimuli via the dorsal vagal complex in the brain. The vagovagal reflex controls contraction of the gastrointestinal muscle layers in response to distension of the tract by food. This reflex also allows for the accommodation of large amounts of food in the gastrointestinal tracts.
Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
The cholinergic anti-inflammatory pathway regulates the innate immune response to injury, pathogens, and tissue ischemia. It is the efferent, or motor arm of the inflammatory reflex, the neural circuit that responds to and regulates the inflammatory response.
Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.
The axon reflex is the response stimulated by peripheral nerves of the body that travels away from the nerve cell body and branches to stimulate target organs. Reflexes are single reactions that respond to a stimulus making up the building blocks of the overall signaling in the body's nervous system. Neurons are the excitable cells that process and transmit these reflex signals through their axons, dendrites, and cell bodies. Axons directly facilitate intercellular communication projecting from the neuronal cell body to other neurons, local muscle tissue, glands and arterioles. In the axon reflex, signaling starts in the middle of the axon at the stimulation site and transmits signals directly to the effector organ skipping both an integration center and a chemical synapse present in the spinal cord reflex. The impulse is limited to a single bifurcated axon, or a neuron whose axon branches into two divisions and does not cause a general response to surrounding tissue.
Kevin J. Tracey, a neurosurgeon and inventor, is the president and CEO of the Feinstein Institute for Medical Research, professor of neurosurgery and molecular medicine at Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and president of the Elmezzi Graduate School of Molecular Medicine in Manhasset, New York. The Public Library of Science Magazine, PLOS Biology, recognized Tracey in 2019 as one of the most cited researchers in the world.
An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.
A vagal maneuver is an action used to stimulate the parasympathetic nervous system by activating the vagus nerve. The vagus nerve is the longest nerve of the autonomic nervous system and helps regulate many critical aspects of human physiology, including heart rate, blood pressure, sweating, and digestion through the release of acetylcholine. Common maneuvers that activate the vagus nerve include the Valsalva maneuver and carotid sinus massage, which can serve diagnostic or therapeutic functions.
Neural top–down control of physiology concerns the direct regulation by the brain of physiological functions. Cellular functions include the immune system’s production of T-lymphocytes and antibodies, and nonimmune related homeostatic functions such as liver gluconeogenesis, sodium reabsorption, osmoregulation, and brown adipose tissue nonshivering thermogenesis. This regulation occurs through the sympathetic and parasympathetic system, and their direct innervation of body organs and tissues that starts in the brainstem. There is also a noninnervation hormonal control through the hypothalamus and pituitary (HPA). These lower brain areas are under control of cerebral cortex ones. Such cortical regulation differs between its left and right sides. Pavlovian conditioning shows that brain control over basic cell level physiological function can be learned.
Semapimod (INN), formerly known as CNI-1493, is an investigational new drug which has anti-inflammatory, anti-cytokine, immunomodulatory, antiviral and antimalarial properties.