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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. [1]
In 1987, a study showed that administration of armin, an irreversible inhibitor of acetylcholinesterase, by injection 24 hours before sepsis modelling invoked essential depression of a lethality of mice from experimental infectious process. [2] Later (in 1995) this data has been confirmed at cholinergic stimulation by other cholinomimetics. [3] Inhibitors of acetylcholinesterase can cause higher accessibility of acetylcholine and activation of cholinergic anti-inflammatory pathway as well.
Tumor necrosis factors (TNF) (and other cytokines) are produced by cells of the innate immune system during local injury and infection. These contribute to initiating a cascade of mediator release, and recruiting inflammatory cells to the site of infection to contain infection, referred to as "innate immunity.". TNF amplifies and prolongs the inflammatory response by activating other cells to release interleukin-1 (IL-1), high mobility group B1 (HMGB1) and other cytokines. [4] These inflammatory cytokine responses confer protective advantages to the host at the site of bacterial infection. A “beneficial” inflammatory response is limited, resolves in 48–72 hours, and does not spread systemically. The cholinergic anti-inflammatory pathway provides a braking effect on the innate immune response which protects the body against the damage that can occur if a localized inflammatory response spreads beyond the local tissues, which results in toxicity or damage to the kidney, liver, lungs, and other organs. [5]
The vagus nerve is the tenth cranial nerve. It regulates heart rate, broncho-constriction, digestion, and the innate immune response. The vagus nerve innervates the celiac ganglion, the site of origin of the splenic nerve. Stimulation of the efferent vagus nerve slows heart rate, induces gastrointestinal motility, and inhibits TNF production in spleen. [1] Stimulation of the efferent pathway of the vagus nerve releases acetylcholine, the neurotransmitter which interacts with the α7 subunit of the nicotinic AChR (α7 nAChR). nAChR is expressed on the cell membrane of macrophages and other cytokine secreting cells. Binding of acetylcholine to nAChR activates intracellular signal transduction which inhibits the release of pro-inflammatory cytokines, and promotes the release of anti-inflammatory cytokines, such as interleukin-10 (IL-10). [6]
Inflammatory markers tend to be elevated in people who experience various forms of psychological stress. [7] [8] Psychological stress increases activation in the sympathetic branch of the autonomic nervous system (ANS) resulting in increased adrenergic input to the spleen via sympathetic nerve fibers descending into lymphoid tissues. [9] [10] The main neural structure responsible for down-regulating psychological stress levels is the prefrontal cortex (PFC). The PFC counters sympathetic nervous system activation by inhibiting arousal-eliciting activity in pre-autonomic neural structures such as the amygdala [11] and hypothalamus [12] and by increasing activity in the vagal branch of the ANS. [13] Thus, the prefrontal input to the ANS modulate the inflammatory response to psychological stress in part via the cholinergic anti-inflammatory pathway. [14] In recent years, this PFC-Vagus Nerve-Spleen axis has been linked to cellular senescence [15] [16] and various pathologies such as neurodegenerative diseases and cancer. [17] [18]
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Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors on other cells. It is a member of the tumor necrosis factor superfamily, a family of transmembrane proteins that are cytokines, chemical messengers of the immune system. Excessive production of TNF plays a critical role in several inflammatory diseases, and TNF-blocking drugs are often employed to treat these diseases.
Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
The innate immune system 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, prokaryotes, and invertebrates.
Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.
The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.
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.
An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.
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 the Zucker School of Medicine, 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.
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.
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.
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.
Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.
Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.
Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.
PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRC5- and NLRP12-PANoptosomes, have been characterized so far.