Neuroimmune system

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Neuroimmune system
Glial ntox review.jpg
This diagram depicts the neuroimmune mechanisms that mediate methamphetamine-induced neurodegeneration in the human brain. [1] The NF-κB-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the blood–brain barrier arises through its binding at and activation of sigma-1 receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate transporters (specifically, EAAT1 and EAAT2) and glucose metabolism, and excessive calcium influx in glial cells and dopamine neurons. [1] [2] [3]
Details
System Neuroimmune
Identifiers
MeSH D015213
Anatomical terminology

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 (e.g., the blood–brain barrier and blood–cerebrospinal fluid barrier), mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens. [2] [4] [5]

Contents

The neuroimmune system and peripheral immune system are structurally distinct. Unlike the peripheral system, the neuroimmune system is composed primarily of glial cells; [1] [5] among all the hematopoietic cells of the immune system, only mast cells are normally present in the neuroimmune system. [6] However, during a neuroimmune response, certain peripheral immune cells are able to cross various blood or fluid–brain barriers in order to respond to pathogens that have entered the brain. [2] For example, there is evidence that following injury macrophages and T cells of the immune system migrate into the spinal cord. [7] Production of immune cells of the complement system have also been documented as being created directly in the central nervous system. [8]

Structure

The key cellular components of the neuroimmune system are glial cells, including astrocytes, microglia, and oligodendrocytes. [1] [2] [5] Unlike other hematopoietic cells of the peripheral immune system, mast cells naturally occur in the brain where they mediate interactions between gut microbes, the immune system, and the central nervous system as part of the microbiota–gut–brain axis. [6]

G protein-coupled receptors that are present in both CNS and immune cell types and which are responsible for a neuroimmune signaling process include: [4]

Cellular physiology

The neuro-immune system, and study of, comprises an understanding of the immune and neurological systems and the cross-regulatory impacts of their functions. [9] Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis.[ medical citation needed ] Cytokines have also been implicated in the coordination between the nervous and immune systems. [10] Instances of cytokine binding to neural receptors have been documented between the cytokine releasing immune cell IL-1 β and the neural receptor IL-1R. [10] This binding results in an electrical impulse that creates the sensation of pain. [10] Growing evidence suggests that auto-immune T-cells are involved in neurogenesis. Studies have shown that during times of adaptive immune system response, hippocampal neurogenesis is increased, and conversely that auto-immune T-cells and microglia are important for neurogenesis (and so memory and learning) in healthy adults. [11]

The neuroimmune system uses complementary processes of both sensory neurons and immune cells to detect and respond to noxious or harmful stimuli. [10] For example, invading bacteria may simultaneously activate inflammasomes, which process interleukins (IL-1 β), and depolarize sensory neurons through the secretion of hemolysins. [10] [12] Hemolysins create pores causing a depolarizing release of potassium ions from inside the eukaryotic cell and an influx of calcium ions. [10] Together this results in an action potential in sensory neurons and the activation of inflammasomes. [10]

Injury and necrosis also cause a neuroimmune response. The release of adenosine triphosphate (ATP) from damaged cells binds to and activates both P2X7 receptors on macrophages of the immune system, and P2X3 receptors of nociceptors of the nervous system. [10] This causes the combined response of both a resulting action potential due to the depolarization created by the influx of calcium and potassium ions, and the activation of inflammasomes. [10] The produced action potential is also responsible for the sensation of pain, and the immune system produces IL-1 β as a result of the ATP P2X7 receptor binding. [10]

Although inflammation is typically thought of as an immune response, there is an orchestration of neural processes involved with the inflammatory process of the immune system. Following injury or infection, there is a cascade of inflammatory responses such as the secretion of cytokines and chemokines that couple with the secretion of neuropeptides (such as substance P) and neurotransmitters (such as serotonin). [7] [10] [12] Together, this coupled neuroimmune response has an amplifying effect on inflammation. [10]

Neuroimmune responses

Neuron-glial cell interaction

Different types of glial cells including microglia, astroglia and oligodendrocytes. 1209 Glial Cells of the CNS-02.jpg
Different types of glial cells including microglia, astroglia and oligodendrocytes.

Neurons and glial cells work in conjunction to combat intruding pathogens and injury. Chemokines play a prominent role as a mediator between neuron-glial cell communication since both cell types express chemokine receptors. [7] For example, the chemokine fractalkine has been implicated in communication between microglia and dorsal root ganglion (DRG) neurons in the spinal cord. [13] Fractalkine has been associated with hypersensitivity to pain when injected in vivo, and has been found to upregulate inflammatory mediating molecules. [13] Glial cells can effectively recognize pathogens in both the central nervous system and in peripheral tissues. [14] When glial cells recognize foreign pathogens through the use of cytokine and chemokine signaling, they are able to relay this information to the CNS. [14] The result is an increase in depressive symptoms. [14] Chronic activation of glial cells however leads to neurodegeneration and neuroinflammation. [14]

Microglial cells are of the most prominent types of glial cells in the brain. One of their main functions is phagocytozing cellular debris following neuronal apoptosis. [14] Following apoptosis, dead neurons secrete chemical signals that bind to microglial cells and cause them to devour harmful debris from the surrounding nervous tissue. [14] Microglia and the complement system are also associated with synaptic pruning as their secretions of cytokines, growth factors and other complements all aid in the removal of obsolete synapses. [14]

Astrocytes are another type of glial cell that among other functions, modulate the entry of immune cells into the CNS via the blood–brain barrier (BBB). [14] Astrocytes also release various cytokines and neurotrophins that allow for immune cell entry into the CNS; these recruited immune cells target both pathogens and damaged nervous tissue. [14]

Reflexes

Withdrawal reflex

Withdrawal reflex Imgnotracat arc reflex eng.svg
Withdrawal reflex

The withdrawal reflex is a reflex that protects an organism from harmful stimuli. [12] This reflex occurs when noxious stimuli activate nociceptors that send an action potential to nerves in the spine, which then innervate effector muscles and cause a sudden jerk to move the organism away from the dangerous stimuli. [10] The withdrawal reflex involves both the nervous and immune systems. [10] When the action potential travels back down the spinal nerve network, another impulse travels to peripheral sensory neurons that secrete amino acids and neuropeptides like calcitonin gene-related peptide (CGRP) and Substance P. [10] [12] These chemicals act by increasing the redness, swelling of damaged tissues, and attachment of immune cells to endothelial tissue, thereby increasing the permeability of immune cells across capillaries. [10] [12]

Reflex response to pathogens and toxins

Neuroimmune interactions also occur when pathogens, allergens, or toxins invade an organism. [10] The vagus nerve connects to the gut and airways and elicits nerve impulses to the brainstem in response to the detection of toxins and pathogens. [10] This electrical impulse that travels down from the brain stem travels to mucosal cells and stimulates the secretion of mucus; this impulse can also cause ejection of the toxin by muscle contractions that cause vomiting or diarrhea. [10]

Neuroimmune connections and the vagus nerve have also been highlighted more recently as essential to maintaining homeostasis in the context of novel viruses such as SARS-CoV-2 [15] This is especially relevant when considering the role of the vagus nerve in regulating systemic inflammation via the Cholinergic Anti-inflammatory Pathway. [16]

Reflex response to parasites

The neuroimmune system is involved in reflexes associated with parasitic invasions of hosts. Nociceptors are also associated with the body's reflexes to pathogens as they are in strategic locations, such as airways and intestinal tissues, to induce muscle contractions that cause scratching, vomiting, and coughing. [10] These reflexes are all designed to eject pathogens from the body. For example, scratching is induced by pruritogens that stimulate nociceptors on epidermal tissues. [10] These pruritogens, like histamine, also cause other immune cells to secrete further pruritogens in an effort to cause more itching to physically remove parasitic invaders. [10] In terms of intestinal and bronchial parasites, vomiting, coughing, sneezing, and diarrhea can also be caused by nociceptor stimulation in infected tissues, and nerve impulses originating from the brain stem that innervate respective smooth muscles. [10]

Eosinophils in response to capsaicin, can trigger further sensory sensitization to the molecule. [17] Patients with chronic cough also have an enhanced cough reflex to pathogens even if the pathogen has been expelled. [17] In both cases, the release of eosinophils and other immune molecules cause a hypersensitization of sensory neurons in bronchial airways that produce enhanced symptoms. [10] [17] It has also been reported that increased immune cell secretions of neurotrophins in response to pollutants and irritants can restructure the peripheral network of nerves in the airways to allow for a more primed state for sensory neurons. [10]

Clinical significance

It has been demonstrated that prolonged psychological stress could be linked with increased risk of infection via viral respiratory infection. Studies, in animals, indicate that psychological stress raises glucocorticoid levels and eventually, an increase in susceptibility to streptococcal skin infections. [18]

The neuroimmune system plays a role in Alzheimer's disease. In particular, microglia may be protective by promoting phagocytosis and removal of amyloid-β (Aβ) deposits, but also become dysfunctional as disease progresses, producing neurotoxins, ceasing to clear Aβ deposits, and producing cytokines that further promote Aβ deposition. [19] It has been shown that in Alzheimer's disease, amyloid-β directly activates microglia and other monocytes to produce neurotoxins. [20]

Astrocytes have also been implicated in multiple sclerosis (MS). Astrocytes are responsible for demyelination and the destruction of oligodendrocytes that is associated with the disease. [14] This demyelinating effect is a result of the secretion of cytokines and matrix metalloproteinases (MMP) from activated astrocyte cells onto neighboring neurons. [14] Astrocytes that remain in an activated state form glial scars that also prevent the re-myelination of neurons, as they are a physical impediment to oligodendrocyte progenitor cells (OPCs). [21]

The neuroimmune system is essential for increasing plasticity following a CNS injury via an increase in excitability and a decrease in inhibition, which leads to synaptogenesis and a restructuring of neurons. The neuroimmune system may play a role in recovery outcomes after a CNS injury. [22]

The neuroimmune system is also involved in asthma and chronic cough, as both are a result of the hypersensitized state of sensory neurons due to the release of immune molecules and positive feedback mechanisms. [17]

Preclinical and clinical studies have shown that cellular (microglia/macrophages, leukocytes, astrocytes, and mast cells, etc.) and molecular neuroimmune responses contribute to secondary brain injury after intracerebral hemorrhage. [23] [24]

See also

Related Research Articles

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

<span class="mw-page-title-main">Nervous tissue</span> Main component of the nervous system

Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain and spinal cord, and the peripheral nervous system (PNS) comprising the branching peripheral nerves. It is composed of neurons, also known as nerve cells, which receive and transmit impulses, and neuroglia, also known as glial cells or glia, which assist the propagation of the nerve impulse as well as provide nutrients to the neurons.

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

In cell biology, an effector cell is any of various types of cell that actively responds to a stimulus and effects some change.

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.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

<span class="mw-page-title-main">Glial scar</span> Mass formed in response to injury to the nervous system

A glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

<span class="mw-page-title-main">Robyn S. Klein</span> American neuroimmunologist

Robyn S. Klein is an American neuroimmunologist as well as the Vice Provost and Associate Dean for Graduate Education at Washington University in St. Louis Missouri. Klein is also a professor in the Departments of Medicine, Anatomy & Neurobiology, and Pathology & Immunology. Her research explores the pathogenesis of neuroinflammation in the central nervous system by probing how immune signalling molecules regulate blood brain barrier permeability. Klein is also a fervent advocate for gender equity in STEM, publishing mechanisms to improve gender equity in speakers at conferences, participating nationally on gender equity discussion panels, and through service as the president of the Academic Women’s Network at the Washington University School of Medicine.

<span class="mw-page-title-main">Katerina Akassoglou</span> Greek neuroimmunologist

Katerina Akassoglou is a neuroimmunologist who is a Senior Investigator and Director of In Vivo Imaging Research at the Gladstone Institutes. Akassoglou holds faculty positions as a Professor of Neurology at the University of California, San Francisco. Akassoglou has pioneered investigations of blood-brain barrier integrity and development of neurological diseases. She found that compromised blood-brain barrier integrity leads to fibrinogen leakage into the brain inducing neurodegeneration. Akassoglou is internationally recognized for her scientific discoveries.

<span class="mw-page-title-main">Marion Buckwalter</span> American neurologist

Marion Buckwalter is an American neurologist and neuroscientist and Professor of Neurology and Neurosurgery at the Stanford University School of Medicine. Buckwalter studies how inflammatory responses affect brain recovery after injury or insult, with a specific emphasis on the neuroimmune and glial cell response after stroke.

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

References

  1. 1 2 3 4 Beardsley PM, Hauser KF (2014). "Glial Modulators as Potential Treatments of Psychostimulant Abuse". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. pp. 1–69. doi:10.1016/B978-0-12-420118-7.00001-9. ISBN   9780124201187. PMC   4103010 . PMID   24484974. Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants
  2. 1 2 3 4 Loftis JM, Janowsky A (2014). "Neuroimmune Basis of Methamphetamine Toxicity". Neuroimmune Signaling in Drug Actions and Addictions. pp. 165–197. doi:10.1016/B978-0-12-801284-0.00007-5. ISBN   9780128012840. PMC   4418472 . PMID   25175865. Collectively, these pathological processes contribute to neurotoxicity (e.g., increased BBB permeability, inflammation, neuronal degeneration, cell death) and neuropsychiatric impairments (e.g., cognitive deficits, mood disorders){{cite book}}: |journal= ignored (help)
    "Figure 7.1: Neuroimmune mechanisms of methamphetamine-induced CNS toxicity"
  3. ↑ Kaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC   3137201 . PMID   21886562.
  4. 1 2 Rogers TJ (2012). "The molecular basis for neuroimmune receptor signaling". J Neuroimmune Pharmacol. 7 (4): 722–4. doi:10.1007/s11481-012-9398-4. PMC   4011130 . PMID   22935971.
  5. 1 2 3 Gimsa U, Mitchison NA, Brunner-Weinzierl MC (2013). "Immune privilege as an intrinsic CNS property: astrocytes protect the CNS against T-cell-mediated neuroinflammation". Mediators Inflamm. 2013: 1–11. doi: 10.1155/2013/320519 . PMC   3760105 . PMID   24023412. Astrocytes have many functions in the central nervous system (CNS). ... they are responsible for formation of the blood-brain barrier (BBB) and make up the glia limitans. Here, we review their contribution to neuroimmune interactions and in particular to those induced by the invasion of activated T cells. ... Within the central nervous system (CNS), astrocytes are the most abundant cells.
  6. 1 2 Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC (2015). "Mast cells in meningiomas and brain inflammation". J Neuroinflammation. 12 (1): 170. doi: 10.1186/s12974-015-0388-3 . PMC   4573939 . PMID   26377554. MCs originate from a bone marrow progenitor and subsequently develop different phenotype characteristics locally in tissues. Their range of functions is wide and includes participation in allergic reactions, innate and adaptive immunity, inflammation, and autoimmunity [34]. In the human brain, MCs can be located in various areas, such as the pituitary stalk, the pineal gland, the area postrema, the choroid plexus, thalamus, hypothalamus, and the median eminence [35]. In the meninges, they are found within the dural layer in association with vessels and terminals of meningeal nociceptors [36]. MCs have a distinct feature compared to other hematopoietic cells in that they reside in the brain [37]. MCs contain numerous granules and secrete an abundance of prestored mediators such as corticotropin-releasing hormone (CRH), neurotensin (NT), substance P (SP), tryptase, chymase, vasoactive intestinal peptide (VIP), vascular endothelial growth factor (VEGF), TNF, prostaglandins, leukotrienes, and varieties of chemokines and cytokines some of which are known to disrupt the integrity of the blood-brain barrier (BBB) [38–40].

    They key role of MCs in inflammation [34] and in the disruption of the BBB [41–43] suggests areas of importance for novel therapy research. Increasing evidence also indicates that MCs participate in neuroinflammation directly [44–46] and through microglia stimulation [47], contributing to the pathogenesis of such conditions such as headaches, [48] autism [49], and chronic fatigue syndrome [50]. In fact, a recent review indicated that peripheral inflammatory stimuli can cause microglia activation [51], thus possibly involving MCs outside the brain.
  7. 1 2 3 Ji, Ru-Rong; Xu, Zhen-Zhong; Gao, Yong-Jing (2014). "Emerging targets in neuroinflammation-driven chronic pain". Nature Reviews Drug Discovery. 13 (7): 533–548. doi:10.1038/nrd4334. PMC   4228377 . PMID   24948120.
  8. ↑ Stephan, Alexander H.; Barres, Ben A.; Stevens, Beth (2012-01-01). "The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease". Annual Review of Neuroscience. 35 (1): 369–389. doi:10.1146/annurev-neuro-061010-113810. PMID   22715882. S2CID   2309037.
  9. ↑ Brady, Scott T.; Siegel, George J. (2012-01-01). Basic Neurochemistry: Principles of Molecular, Cellular and Medical Neurobiology. Academic Press. ISBN   9780123749475.
  10. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Talbot, Sébastien; Foster, Simmie; Woolf, Clifford (February 22, 2016). "Neuroimmune Physiology and Pathology". Annual Review of Neuroscience. 34: 421–47. doi:10.1146/annurev-immunol-041015-055340. PMID   26907213.
  11. ↑ Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006). "Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood". Nat. Neurosci. 9 (2): 268–75. doi:10.1038/nn1629. PMID   16415867. S2CID   205430936.
  12. 1 2 3 4 5 McMahon, Stephen; La Russa, Federica; Bennett, David (June 19, 2015). "Crosstalk between the nociceptive and immune systems in host defence and disease". Nature Reviews Neuroscience. 16 (7): 389–402. doi:10.1038/nrn3946. PMID   26087680. S2CID   22294761.
  13. 1 2 Miller, Richard; Hosung, Jung; Bhangoo, Sonia; Fletcher, White (2009). Sensory Nerves. Heidelberg, Germany: Springer. pp. 417–449. ISBN   978-3-540-79090-7.
  14. 1 2 3 4 5 6 7 8 9 10 11 Tian, Li; Ma, Li; Kaarela, Tiina; Li, Zhilin (July 2, 2012). "Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases". Journal of Neuroinflammation. 9: 155. doi: 10.1186/1742-2094-9-155 . PMC   3410819 . PMID   22747919.
  15. ↑ Rangon, Claire-Marie; Niezgoda, Adam (2022-07-29). "Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics". Bioengineering. 9 (8): 352. doi: 10.3390/bioengineering9080352 . ISSN   2306-5354. PMC   9405360 . PMID   36004877.
  16. ↑ Rosas-Ballina, M.; Tracey, K. J. (June 2009). "Cholinergic control of inflammation". Journal of Internal Medicine. 265 (6): 663–679. doi:10.1111/j.1365-2796.2009.02098.x. PMC   4540232 . PMID   19493060.
  17. 1 2 3 4 Chung, Kian (October 2014). "Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome". Journal of Thoracic Disease. 6 (Suppl 7): S699–707. doi:10.3978/j.issn.2072-1439.2014.08.41. PMC   4222934 . PMID   25383203.
  18. ↑ Kawli, Trupti; He, Fanglian; Tan, Man-Wah (2010-01-01). "It takes nerves to fight infections: insights on neuro-immune interactions from C. elegans". Disease Models & Mechanisms. 3 (11–12): 721–731. doi:10.1242/dmm.003871. ISSN   1754-8403. PMC   2965399 . PMID   20829562.
  19. ↑ Farfara, D.; Lifshitz, V.; Frenkel, D. (2008). "Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease". Journal of Cellular and Molecular Medicine. 12 (3): 762–780. doi:10.1111/j.1582-4934.2008.00314.x. ISSN   1582-1838. PMC   4401126 . PMID   18363841.
  20. ↑ Hickman SE, El Khoury J (2013). "The neuroimmune system in Alzheimer's disease: the glass is half full". J. Alzheimers Dis. 33 (Suppl 1): S295–302. doi:10.3233/JAD-2012-129027. PMC   8176079 . PMID   22751176.
  21. ↑ Nair, Aji; Frederick, Terra; Miller, Stephen (September 2008). "Astrocytes in Multiple Sclerosis: a Product of their environment". Cellular and Molecular Life Sciences. 65 (17): 2702–20. doi:10.1007/s00018-008-8059-5. PMC   2858316 . PMID   18516496.
  22. ↑ O’Reilly, Micaela L.; Tom, Veronica J. (2020). "Neuroimmune System as a Driving Force for Plasticity Following CNS Injury". Frontiers in Cellular Neuroscience. 14: 187. doi: 10.3389/fncel.2020.00187 . ISSN   1662-5102. PMC   7390932 . PMID   32792908.
  23. ↑ Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J (May 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". J Cereb Blood Flow Metab. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC   7446569 . PMID   32423330.
  24. ↑ Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610. doi:10.1016/j.pneurobio.2019.03.003. PMID   30923023. S2CID   85495400.

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