Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis

Abstract

Mast cells are localized throughout the body and mediate allergic, immune, and inflammatory reactions. They are heterogeneous, tissue-resident, long-lived, and granulated cells. Mast cells increase their numbers in specific site in the body by proliferation, increased recruitment, increased survival, and increased rate of maturation from its progenitors. Mast cells are implicated in brain injuries, neuropsychiatric disorders, stress, neuroinflammation, and neurodegeneration. Brain mast cells are the first responders before microglia in the brain injuries since mast cells can release prestored mediators. Mast cells also can detect amyloid plaque formation during Alzheimer's disease (AD) pathogenesis. Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation. Stress induces the release of corticotropin-releasing hormone (CRH) from paraventricular nucleus of hypothalamus and mast cells. CRH activates glial cells and mast cells through CRH receptors and releases neuroinflammatory mediators. Stress also increases proinflammatory mediator release in the peripheral systems that can induce and augment neuroinflammation. Post-traumatic stress disorder (PTSD) is a traumatic-chronic stress related mental dysfunction. Currently there is no specific therapy to treat PTSD since its disease mechanisms are not yet clearly understood. Moreover, recent reports indicate that PTSD could induce and augment neuroinflammation and neurodegeneration in the pathogenesis of neurodegenerative diseases. Mast cells play a crucial role in the peripheral inflammation as well as in neuroinflammation due to brain injuries, stress, depression, and PTSD. Therefore, mast cells activation in brain injury, stress, and PTSD may accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases including AD. This review focusses on how mast cells in brain injuries, stress, and PTSD may promote the pathogenesis of AD. We suggest that inhibition of mast cells activation and brain cells associated inflammatory pathways in the brain injuries, stress, and PTSD can be explored as a new therapeutic target to delay or prevent the pathogenesis and severity of AD.

Mast cell infiltration associated with loss of interstitial cells of Cajal and neuronal degeneration in achalasia

“…These agents can act on adjacent inflammatory cells or neurons and cause downstream cascade reactions . Accordingly, mast cells have been confirmed to play an important role in central and peripheral neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Hirschsprung's disease, by mediating immune inflammatory reactions . Among these diseases, the pathology and clinical features of Hirschsprung's disease are very similar to those of achalasia.…”

“…7 Mast cells have been shown to participate in autoimmunemediated neuroinflammation in various disorders, including inflammatory bowel disease, chronic neurodegenerative diseases, and Hirschsprung's disease. 8,9 A recent study reported that mast cells may participate in the autoimmune process in achalasia. 12 However, this issue remains unclear, as no further study has described the relationship between mast cells and achalasia.…”

Elevated zinc transporter ZnT3 in the dentate gyrus of mast cell‐deficient mice

“…Many of the processes attributed to mast cells in the brain have also been connected to zinc (Kempuraj et al., ). Mast cells have been implicated in responding to brain injury and stress but the long‐term consequences of their actions in the brain are not well understood (Kempuraj et al., ). The concentration of zinc in mast cells is high, so we initially expected that mast cell‐deficient mice would have less zinc in their brains.…”

Acute-stress impairs cytoprotective mechanisms through neural inhibition of the insulin pathway

“…In humans, persistent experience of either real or perceived danger has been associated with adverse health, and premature death (81,82) (17). For example, patients that suffer from post-traumatic stress disorder (PTSD) exhibit high risks of neurodegenerative, cardiovascular, respiratory and gastrointestinal diseases, immune dysfunction and premature aging (83)(84)(85)(86). Severity of PTSD symptoms correlates with high levels of noradrenaline, suggesting that increased sympathetic arousal may be closely linked to the dysregulation of body fitness (87)(88)(89).…”