Neuroimmune system

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Neuroimmune system
glial cells and dopamine neurons.[1][2][3]
Details
SystemNeuroimmune
Identifiers
MeSHD015213
Anatomical terminology]

The neuroimmune system is a system of structures and processes involving the

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

The neuroimmune system and peripheral immune system are structurally distinct. Unlike the peripheral system, the neuroimmune system is composed primarily of

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

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]

Neuroimmunity is additionally mediated by the enteric nervous system, namely the interactions of enteric neurons and glial cells. These engage with enteroendocrine cells and local macrophages, sensing signals from the gut lumen, including those from the microbiota. These signals prompt local immune responses and transmit to the CNS through humoral and neural pathways. Interleukins and signals from immune cells can access the hypothalamus via the neurovascular unit or circumventricular organs.[9]

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.

IL-1 β and the neural receptor IL-1R.[11] This binding results in an electrical impulse that creates the sensation of pain.[11] 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.[12]

The neuroimmune system uses complementary processes of both

IL-1 β), and depolarize sensory neurons through the secretion of hemolysins.[11][13] Hemolysins create pores causing a depolarizing release of potassium ions from inside the eukaryotic cell and an influx of calcium ions.[11] Together this results in an action potential in sensory neurons and the activation of inflammasomes.[11]

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.[11] 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.[11] 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.[11]

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][11][13] Together, this coupled neuroimmune response has an amplifying effect on inflammation.[11]

Neuroimmune responses

Neuron-glial cell interaction

Different types of glial cells including microglia, astroglia and oligodendrocytes.

Neurons and glial cells work in conjunction to combat intruding pathogens and injury.

neurodegeneration and neuroinflammation.[15]

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.[15] Following apoptosis, dead neurons secrete chemical signals that bind to microglial cells and cause them to devour harmful debris from the surrounding nervous tissue.[15] 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.[15]

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).[15] 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.[15]

Reflexes

Withdrawal reflex

Withdrawal reflex

The withdrawal reflex is a reflex that protects an organism from harmful stimuli.[13] 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.[11] The withdrawal reflex involves both the nervous and immune systems.[11] 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.[11][13] 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.[11][13]

Reflex response to pathogens and toxins

Neuroimmune interactions also occur when pathogens, allergens, or toxins invade an organism.[11] 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.[11] 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.[11]

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 [16] This is especially relevant when considering the role of the vagus nerve in regulating systemic inflammation via the Cholinergic Anti-inflammatory Pathway. [17]

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.

smooth muscles.[11]

Eosinophils in response to capsaicin, can trigger further sensory sensitization to the molecule.[18] Patients with chronic cough also have an enhanced cough reflex to pathogens even if the pathogen has been expelled.[18] In both cases, the release of eosinophils and other immune molecules cause a hypersensitization of sensory neurons in bronchial airways that produce enhanced symptoms.[11][18] 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.[11]

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.[19]

The neuroimmune system plays a role in

neurotoxins.[21]

Astrocytes have also been implicated in

demyelination and the destruction of oligodendrocytes that is associated with the disease.[15] This demyelinating effect is a result of the secretion of cytokines and matrix metalloproteinases (MMP) from activated astrocyte cells onto neighboring neurons.[15] 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).[22]

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.[23]

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.[18]

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.[24][25]

See also

References

  1. ^
    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. ^
    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
    "
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  5. ^ . 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. ^ . 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.
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Further reading

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