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

Duraaisamy Kempuraj et al.

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This document delves into the role of mast cells in neuroinflammation, a topic gaining increased attention in the context of neurodegenerative diseases. This work builds upon the established understanding of mast cells as immune modulators, expanding their role from peripheral allergic and inflammatory responses to their involvement in central nervous system disorders. Prior research has implicated neuroinflammation in the pathogenesis of Alzheimer's disease (AD), and this research seeks to connect mast cell activation in conditions like brain injury, stress, and post-traumatic stress disorder (PTSD) to the acceleration of AD. By exploring the mechanisms through which mast cells contribute to neuroinflammation, this study aims to identify potential therapeutic targets for preventing or delaying the onset and progression of AD, addressing a critical unmet need in the field.

Definition

Prestored mediators: These are pre-synthesized molecules, such as histamine and TNF-α, stored within mast cell granules and rapidly released upon activation. This allows for an immediate response to stimuli.

Open Access Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience Received: 10 July 2017 Accepted: 30 November 2017 Published: 12 December 2017 Citation: Kempuraj D, Selvakumar G.P., Thangavel R, Ahmed M.E., Zaheer S, Raikwar S.P., Iyer S.S., Bhagavan S.M., Beladakere-Ramaswamy S and Zaheer A (2017) Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis. Front. Neurosci. 11:703. doi: 10.3389/fnins 2017..00703 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 (A.D.) 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 (C.R.H.) from paraventricular nucleus of hypothalamus and mast cells. C.R.H. activates glial cells and mast cells through C.R.H. 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 (P.T.S.D.) is a traumatic-chronic stress related mental dysfunction. Currently there is no specific therapy to treat P.T.S.D. since its disease mechanisms are not yet clearly understood. Moreover, recent reports indicate that P.T.S.D. 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 P.T.S.D. Therefore, mast cells activation in brain injury, stress, and P.T.S.D. may accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases including A.D. This review focuses on how mast cells in brain injuries, stress, and P.T.S.D. may promote the pathogenesis of A.D. We suggest that inhibition of mast cells activation and brain cells associated inflammatory pathways in the brain injuries, stress, and P.T.S.D. can be explored as a new therapeutic target to delay or prevent the pathogenesis and severity of A.D.

Introduction

Definition

MMCPs: Mouse Mast Cell Proteases, a group of proteases expressed in mouse mast cells, used to classify them as connective tissue mast cells (CTMC) or mucosal type mast cells (MMC).

Mast cells derived from hematopoietic progenitors are multifunctional antigen presenting cells present in the tissues throughout the body. Mast cells are involved in both health and disease conditions by releasing specific inflammatory, anti-inflammatory, and other mediators in tissues. Mast cells are involved in immune responses, inflammation, tissue damage, and repair mechanism of the damaged tissues in peripheral organs and in the central nervous system (C.N.S.). Human mast cells are broadly classified into mucosal type (M.C.T.) and connective tissue type (M.C.T.C.), based upon the type of proteases present in their cytoplasmic granules. The mucosal type of mast cells contain tryptase while the connective tissue type of mast cells contain both tryptase as well as chymase in their cytoplasmic granules. Brain mast cells also show similar heterogeneity. Mouse primary mast cells express various mouse mast cell proteases (M.M.C.P.s) that are different from human mast cell proteases and are classified as connective tissue mast cells (C.T.M.C.) or mucosal type mast cells (M.M.C.) based on the expression of M.M.C.P.'s.

Mast cells play an important role in inflammatory pathogenesis such as anaphylactic reactions, asthma, allergy, arthritis, cardiovascular diseases, systemic mastocytosis, interstitial cystitis, psoriasis, atopic dermatitis, cancer and metastasis, endometriosis, obesity, ulcers, prostatitis, periodontitis, irritable bowel syndrome (I.B.S.), and inflammatory bowel disease (I.B.D.). Additionally, we and others have shown that mast cells are also implicated in many neurological and neuroinflammatory conditions including brain injury, traumatic brain injury (T.B.I.), stroke, Multiple sclerosis (M.S.), Experimental Autoimmune Encephalomyelitis (E.A.E.), Parkinson's disease (P.D.), dementia, Alzheimer's disease (A.D.), intracerebral hemorrhage (I.C.H.), neuropsychiatric disorders, stress conditions, sleep disorders, migraine, pain, headache, attention deficit disorder, autism, joint and muscle pain, and itching. Mast cell-derived inflammatory mediators increase blood brain barrier (B.B.B.) permeability and activate brain resident immune cells such as microglia. Further, mast cell mediators increase vascular permeability and increase escape and recruitment of immune and inflammatory cells at the site of injury. Optimal inflammatory responses or physiological levels of inflammatory mediators are beneficial and protect the body as they remove unwanted waste materials and repair the damaged tissues. However, excessive and chronic inflammatory responses can lead to increased inflammatory mediator levels, severe inflammation and tissue injury. Mast cells grow in numbers by increased proliferation, increased recruitment, increased survival, and accelerated maturation from their progenitors during inflammatory conditions. Mast cells are ubiquitous in the body, but they are highly concentrated in the regions where the body is directly exposed to the outer environment, and also in inflammatory and allergic tissues. Thus, mast cells participate in the first line of defense from the invading pathogenic organisms and other environmental factors including pollutants. Further, mast cells are one of the fastest responders by releasing prestored and newly synthesized mediators among immune and inflammatory cells. Mast cells are reported as the cells that are ready to battle any time with any kind of threats to the body, since their cytoplasmic secretory granules are filled with several preformed as well as preactivated immune and inflammatory mediators including histamine, tryptase, chymase, tumor necrosis factor-alpha (T.N.F.-α), serotonin, heparin, proteoglycans, and vascular endothelial growth factor (V.E.G.F.). Mast cells can generate and release reactive oxygen species (R.O.S.) within seconds of its activation. Mast cells are powerful and rapid sensors of tissue injury/necrosis, infectious agents, and inflammation since they are located in the host-environment boundaries and express pattern recognition receptors and cytokines such as local alarmin, interleukin-33 (I.L.-33) (Martin and Martin, 2016). Mast cells detect and rapidly respond to protect from cellular injuries by detecting I.L.-33 released from the damaged cells. Mast cells not only sense the cellular microenvironment in the tissues but also sense and respond to external environment such as cold, hot, humidity, pressure, allergen, and toxins.

Mast cells are highly armed defensive system similar to our soldiers and police, protecting the body from outside and inside threats, including invasion of infectious agents, parasites, injuries, and toxins. Mast cells perform these functions rapidly by releasing prestored mediators from their granules and by synthesizing and secreting specific new chemical substances/mediators as required in acute and chronic immune responses. Mast cell committed hematopoietic progenitors from bone marrow enters into the bloodstream, gets transported into the tissues/organs, settles there and matures into specific type of mast cells depending upon the type of tissue and microenvironment, with local specific growth factors and the specific needs/threat of that particular tissue.

For example, the mast cells present in the skin are connective tissue type, and mast cells present in the lung are mucosal type. Connective tissue type of mast cells can respond extensively to neuropeptides such as substance P and neurotensin. However, mast cells are interchangeable and thus can transform into another phenotype whenever needed in the body.

Moreover, mast cells travel to another region or tissue, settle there and sense the new tissue microenvironment, and then proliferate to increase specific mast cell type based upon the requirement. Factors like infections locally and transiently increases the accumulation of mast cell progenitors and increases mast cell numbers (Zarnegar et al., 2017). Mast cells even migrate in to the brain from peripheral organs through B.B.B. and proliferate in the brain during neuroinflammatory conditions.

Mast cell activation leads to the release of specific inflammatory mediators such as T.N.F.-α, I.L.-1beta, I.L.-8, I.L.-33, chemokine (C-C motif) ligand 2 (C.C.L. 2), C.C.L. 3, C.C.L. 5, granulocyte macrophage colony-stimulating factor (G.M.-C.S.F.), V.E.G.F., matrix metalloproteinase (M.M.P.s), R.O.S., substance P (S.P.), stem cell factor (S.C.F.), nerve growth factor N.G.F., dopamine, transforming growth factor-beta T.G.F.beta, corticotrophin-releasing hormone (C.R.H.), neurotensin, histamine, prostaglandin D.2. (P.G.D. 2), leukotrienes L.T.'s, proteases tryptase and chymase based upon the type of mast cells and type of stimuli in the tissues. Mast cells express receptors and ligands for various immune and inflammation related pathways including C.R.H., S.P., C.D. 40, C.D.40.L., S.C.F., cytokines, and chemokines. About 25% of rat mast cell granule content is T.N.F.-α that is neurotoxic (Hendriksen et al., 2017). Inflammatory pathways in the brain with many of the above-mentioned mediators lead to neuroinflammation, which is an important process in the onset and progression of A.D., P.D., and M.S. C-reactive protein (C.R.P.), a marker of inflammation is implicated in mood disorders, cognitive disorders and A.D., and Post-Traumatic Stress Disorder (P.T.S.D.) (Solomon et al., 2017). A recent study showed increased blood levels of inflammatory markers I.L.-1beta, T.N.F.-α, I.L.-6, and I.L.-10 in Lewy body dementia L.B.D. and increased C.R.P. in P.D. dementia patients. Another recent review reported possible peripheral inflammatory markers in A.D. patients. This report combined the results from 175 studies, analyzed 51 inflammatory markers in A.D. patients, and compared with control subjects. They reported increased peripheral levels of T.N.F.-α converting enzyme, I.L.-1beta, I.L.-2, I.L.-6, I.L.-18, interferon-gamma I.F.N.gamma, homocysteine, high-sensitivity C.R.P., C.C.L. 10, epidermal growth factor E.G.F., vascular cell adhesion molecule-1 V.A.C.M.-1, T.N.F. receptor1/2, and alpha1-antichymotrypsin in A.D. patients as compared with the levels in the control subjects. This study suggests that A.D. pathogenesis is associated with peripheral immune and inflammatory responses, and increased I.L.-6 levels may be used as a biomarker to correlate with the severity of cognitive impairment in A.D. patients. Further, another inflammatory pathway marker transcription factor, nuclear factor kappa B N.F.k.B. activity has been shown to be increased in the brains of A.D. patients.

Mast cells are present adjacent to the neurons and glial cells in thalamus, hypothalamus, and leptomeninges and activate them by cell-to-cell contacts as well as by releasing inflammatory and neurotoxic mediators. Mast cells located at the brain side ( greater than 95%) of the B.B.B. protect the brain from invading pathogens and toxic substances from the peripheral organs. Mast cells play a major role in neuroinflammatory conditions including neurodegenerative diseases, stroke, M.S., T.B.I. by increasing the B.B.B. permeability and activating the brain resident immune cells microglia, and T-cells. Mast cells are implicated in the brain injuries, stress, and P.T.S.D.-induced neuroinflammation that could contribute to the pathogenesis of A.D. as shown in Figure 1. About 50% of histamine in the brain is released from the brain mast cells (Chikahisa et al., 2013). Mast cells activate glial cells and neurons through protease-activated receptor-2 P.A.R.-2 pathway. These findings strongly suggest that mast cells are important mediators of neuroinflammation. Activation of glia is implicated in neuroinflammation-mediated neurodegeneration mechanisms. Several studies have shown that targeting glial cells-mediated neuroinflammation is effective in the treatment of A.D. As mast cells are implicated in brain injury, stress, and P.T.S.D., activation of mast cells in these conditions could increase neuroinflammation and thereby accelerate the onset and progression of A.D. Therefore, the focus of this article is to review currently available data to link the mast cell activation in stress, brain injury, and P.S.T.D. with that of pathogenesis of A.D. We have searched PubMed for studies in this research area using the keywords mast cells, stress, brain injury, P.T.S.D., and A.D.

Figure 1 summary: The figure is a schematic diagram. It illustrates the relationship between mast cells, brain injury, stress, post-traumatic stress disorder, and neurodegeneration in Alzheimer's disease pathogenesis. The diagram shows that brain injury, stress, and post-traumatic stress disorder activate mast cells and microglia, leading to the release of inflammatory mediators. These mediators contribute to increased blood-brain barrier permeability, neuroinflammation, neurodegeneration, increased levels of amyloid beta, and accelerated Alzheimer's disease pathogenesis. The figure suggests a complex interplay between these factors in the development of Alzheimer's disease.

Brain Injury, Mast Cells, and Inflammation

Neuroinflammation plays central role in the C.N.S. disorders such as M.S., P.D., A.D., brain and spinal cord injuries, stroke, depression, schizophrenia, and chronic pain. Increased levels of proinflammatory cytokines and chemokines also induce behavioral and pathological changes in the brain disorders such as A.D. and stroke. T.B.I. is an important cause of morbidity and mortality in veterans. The initial neuroinflammatory responses after the primary brain injury is beneficial but lingering and chronic immune and neuroinflammatory responses cause additional secondary brain damage. T.B.I. activates glial cells, neurons and immune cells, induces neuroinflammation and neurodegeneration, axonal degeneration, elevates brain and peripheral inflammatory cytokines and chemokines, increases triggering receptor expressed on myeloid cells 2 (T.R.E.M. 2) expression and affects microvascular system. However, studies also suggest suppression of A.D. symptoms after T.B.I. Activation of immune cells and changes in the microvascular unit where mast cells are located upregulates the neuroinflammatory responses. Brain injury causes cognitive impairment, increases the accumulation of amyloid precursor protein A.P.P., extracellular beta amyloid (Aβ) peptide and intracellular neurofibrillary tangles N.F.T.'s consisting of tau protein associated with inflammatory cytokine release (Johnson et al., Gupta and Sen, Kokiko-Cochran et al., Young et al., 2016). T.B.I. is an important risk factor for neurodegenerative diseases such as dementia and A.D.

Substance P released in T.B.I. or under stress, activates mast cells, microglia and astrocytes, and releases additional neuroinflammatory mediators that increase B.B.B. permeability. There is no specific and approved drug to treat T.B.I. One study reported that T.B.I. with loss of consciousness influences Lewy body formation, pathogenesis of P.D. but does not result in dementia and A.D. The first response after T.B.I. is the infiltration and degranulation of mast cells in the brain. Mast cell degranulation releases cytoplasmic granule's prestored histamine and proteases. Mast cells increase B.B.B. permeability and allow inflammatory cell infiltrations in the brain after cerebral ischemic brain injury. Headache associated with mild T.B.I. is due to persistent dural mast cell degranulation and its inflammatory mediator release. Inhibition of mast cell activation could be used as an initial adjuvant therapy to treat hypoxia-ischemia, ischemic stroke, and I.C.H. in new-borns and adults. Increased mast cell numbers and their degranulation-derived histamine mediates ischemia-induced neuronal death in the brain. Mast cell number increases for days and weeks and contributes to the brain damage by releasing inflammatory mediators such as T.N.F. and I.L.-9 in perinatal hypoxic-ischemia and that inhibition of mast cell activation decreased the brain damage in the immature rat brains. Similarly, inhibition of mast cell activation inhibits hemorrhage formation in thrombolytic ischemic stroke in rats (Strbian et al., 2007). Further, T.B.I. has been shown to increase the number of mast cells in the injured cortical area. A recent study reported that mast cells are the first responders in I.C.H. and promote B.B.B. breach, edema formation, recruit inflammatory cells, and amplify brain injury. These findings clearly indicate that mast cells play an important role in the neuroinflammatory responses after the brain injuries or T.B.I. and that the enhanced neuroinflammation can predispose to the pathogenesis of A.D.

Stress, Mast Cells, and Inflammation

Several inflammatory conditions are worsened by stress, and mast cell activation with inflammatory mediator release plays a crucial role in stress-dependent inflammatory mechanism. A recent study showed chronic mild stress for 3 weeks increased the number of mast cells in the brain and disturbed sleep in mice. Interaction between hypothalamus, pituitary, and adrenal gland is an important stress response in neuropsychiatric conditions and depression. Stress activates hypothalamo-pituitary-adrenal (H.P.A.) axis within seconds and increases the release of C.R.H. and arginine vasopressin A.V.P. from the paraventricular nucleus P.V.N. of the hypothalamus in the brain, enhances mast cell activation, vascular permeability, and the expression of C.R.H. receptors. Proinflammatory cytokines also activate H.P.A. axis (Hayley, 2011). Furthermore, stress causes C.R.H. release from hypothalamus into the pituitary gland and releases adrenocorticotropic hormone (A.C.T.H.) from the pituitary gland. A.C.T.H. acts on adrenal cortex to release glucocorticoids, which in turn inhibit the release of C.R.H. and A.C.T.H. in a negative feedback mechanism. C.R.H. and A.C.T.H. directly activate microglia to release neuroinflammatory mediators. Psychological and environmental stress conditions induce the release of C.R.H. C.R.H. also called as corticotropin-releasing factor C.R.F., is a 41 amino acid peptide released from hypothalamic neurons as well as from the activated mast cells (Kato et al., 2013). V.E.G.F., an angiogenic cytokine that plays an important role in inflammation, is also elevated in P.T.S.D. patients. We have shown that stress, C.R.H., mast cell activation, and V.E.G.F. play a crucial role in stress-induced exacerbation of inflammation. Further, peripheral derived C.R.H. also augments stress-mediated effects. We have previously shown that mast cell activation and C.R.H. release under stress conditions increases B.B.B. permeability, and tumor metastases into the brain. Further, stress-induced vascular permeability, an important event in inflammation is reduced in mast cell deficient mice. Acute stress is reported to accelerate the pathogenesis of neuroinflammatory and autoimmune disease E.A.E. in mice.

C.R.H. activates mast cells to release various neuroinflammatory and neurotoxic mediators that leads to a breach of B.B.B. and activates glial cells to release more inflammatory mediators, thereby contributing to the chronic neuroinflammation in the brain. Acute stress increases B.B.B. permeability through brain mast cell activation and C.R.H. release. Microglia express C.R.H. receptors, and activation of microglia by C.R.H. from brain cells causes the release of neurotoxic inflammatory mediators in mental disorders. Activation of rat microglia by C.R.H. through C.R.H.R.1.-induces microglial proliferation and release of T.N.F.- alpha and activation of mitogen-activated protein kinase M.A.P.K.'s. C.R.H. also increases microglial expression of I.L.-18 which is implicated in stress, depression, and P.T.S.D. conditions. A recent report using mast cell and C.R.H.R.1.-deficient mice reported that C.R.H.R. 1 mediates stress-induced mast cell degranulation. Inflammatory mediators released from microglia induce neuronal destruction in neurodegenerative diseases. Several stressors increase aging-like process and activate microglia toward proinflammatory phenotype causing destruction of neurons. Stress conditions clearly activate microglia in the brain. Microglial activation plays an important role in the pathogenesis of neurodegenerative diseases. Microglia and mast cells which develop from hematopoietic progenitors are reported as two tracks to the road to neuroinflammation (Skaper et al., 2012).

We have previously shown that human mast cells synthesize and secrete C.R.H. and express functional C.R.H. receptors (C.R.H.R. 1 and C.R.H.-R2) (Kempuraj et al., 2004; Cao et al., 2005; Papadopoulou et al., 2005). C.R.H. released from mast cell acts in an autocrine as well as paracrine manner to activate mast cells and glial cells in the C.N.S. in stress and neuroinflammatory conditions. Social stressful experience is associated with psychiatric disorders with enhanced inflammatory responses. The level of stress-related pathology varies from one person to another, due to the differences in the levels of immune and inflammatory response specifically mast cell response to various stressors and activation signals. Patients with depression exhibit elevated proinflammatory cytokine levels in the plasma and cerebrospinal fluid C.S.F. Microglial activation is increased in the brains of depressed patients and this increase is correlated with the severity of the depression. Social stress and depression can affect anyone at any age, gender, ethnicity, and socio-economic background. Previous reports suggest that stress, depression and P.S.T.D. are more prevalent in female than male patients.

Psychological and environmental stress induces or worsens anxiety and depression, activates neurons, microglia, and induces neuronal dystrophy. Stress due to cold worsens neuroinflammation, induces oxidative stress, neuronal autophagy, and enhances immune responses. Mast cells are linked with inflammatory pathways leading to chronic depression in mastocytosis patients. Mastocytosis patients also show increased oxidative stress markers of inflammation. Stress worsens several conditions such as migraines, by activating mast cells to release inflammatory mediators. Stress is undoubtedly linked to the severity of neurodegenerative disorders. Work-related stress such as job security, job environment and lack of job satisfaction increases the risk for vascular dementia and A.D. C.R.H. released in stressful conditions is protective at a lower concentration, but is harmful at higher concentrations and exacerbates A.D. progression.

Chronic stress can accelerate A.D. pathogenesis in human and animal models through increases in inflammatory responses, Aβ accumulation, tau hyperphosphorylation, oxidative stress, mitochondrial impairment, and glucose metabolism. Stress in early-life increases the risk of cognitive disorders in the aged mouse model of A.D. Early life chronic stress in transgenic A.P.P./P.S. 1 A.D. mice from postnatal day 2 to 9 has been shown to increase Aβ pathology, neuroinflammatory mediators, and neuroinflammatory responses in 4 and 10 months-old mice as compared to age matched-wild type mice. Additionally, early life stress induced both immediate as well as late effects; increased inflammatory responses, C.D. 68 expression and neuroinflammatory levels in the hippocampus in an age-dependent manner in A.D. mouse model. Adolescent stage stress exposure affects brain development, causes depression and brain dysfunctions in the adulthood. Chronic stress conditions create a vicious cycle of increased microglial dysfunction associated with decreased clearance, and increased Aβ accumulation exacerbating neuroinflammation and neurodegeneration. The mechanism that chronic stress contributes to microglia-mediated neuroinflammation and cognitive impairments in A.D. is not yet clearly known and that therapeutic interventions to stress-mediated effects could delay the onset, progression, and severity of A.D. (Piirainen et al., 2017). C.D. 33, C.D. 36, and T.R.E.M. 2 are implicated in stress and A.D. progression and that stressful conditions exacerbate Aβ pathology in the animal models of A.D. Increased cortisol levels and H.P.A. axis dysregulation have been implicated in stress conditions and A.D. Chronic stress has been shown to release more Aβ, trigger and worsen A.D. severity. A recent study reported that Tg-A.D. mouse model treated with C.R.H.R. 1 antagonist R.121919 showed decreased stress-mediated oxidative damage, prevented the onset of cognitive impairment and dendritic loss and reduced Aβ deposition in the brain. They report that stress hormones activate neuronal oxidative stress, which increases the release of additional stress hormones and cause neuronal damage in the hippocampus in A.D. brains. The authors further suggest that suppression of stress pathways might be an effective therapy for A.D.

Chronic stress and short-term modern life-like stress upregulates A.D. severity in 3xTg-A.D. mice, an animal model of A.D. They report that combined emotional and physical stress lasting for 5h significantly impaired memory in these A.D. mice as compared to wild type mice. Further, these stress conditions reduced the number of dendritic spines and increased Aβ levels in these 3xTg-A.D. mice. Neurotensin, a neuropeptide along with C.R.H. augments mast cell activation and release of excessive inflammatory mediators in stressful situations. Immobilization (restrain) stress induces H.P.A. axis and activates intracranial mast cells to release tryptase, a mast cell specific inflammatory protease within 30 min in rats as shown by light and electron microscopy. Pretreatment of these animals with anti-C.R.H. before stress inhibited intracranial mast cell activation. Chronic psychological stress is a risk factor for dementia and A.D. by inducing microglial proinflammatory status. These reports strongly indicate that mast cells play a crucial role in stress responses associated with inflammation that may predispose to A.D. pathogenesis in high-risk groups.

P.T.S.D., Mast Cells, and Inflammation

P.T.S.D. is a traumatic stress-related emotional disorder associated with chronic low-grade inflammation. P.T.S.D. causes behavioral impairments as well as immunological disorders. P.T.S.D. is an important concern in war veterans and the combat soldiers at the war regions, and they are at a high risk of developing this disorder. U.S. deployed over 2.5 million service members to Iraq since 2001 and about 15% of them developed P.T.S.D. after their combat experience. P.T.S.D. also affects civilians following trauma or loss of family members. P.T.S.D. patients show chronic stress responses along with low-grade inflammatory reactions in the body. Most of the people with trauma did not develop P.T.S.D., but only some people develop P.T.S.D. This is because of the other factors such as stress and socioeconomic factors that may be considered as important risk factors for the pathogenesis of P.T.S.D. However, the exact mechanism of the pathogenesis of P.T.S.D. is not yet clearly known and therefore no effective treatment options are currently available.

Recent studies have shown that immune disorders with excessive inflammatory reactions are present in P.T.S.D. patients. Additionally, mast cells, the soldiers of our body's (innate and acquired) defense system are also dysregulated in the combat soldiers. Therefore, it is necessary to urgently understand the pathogenesis of P.T.S.D. to take care of our affected defense personnel and to prevent the pathogenesis of P.T.S.D. in general. Several reports strongly suggest elevated neuroinflammation in depressed patients and in chronic stress conditions. Also, behavioral disorders and neuroinflammation are closely linked with peripheral inflammation in social stress model of P.T.S.D.

It has been suggested that P.T.S.D., depression, and stress induces low-grade chronic inflammation that could lead to neurodegenerative diseases. Chronic stress, depression, and P.T.S.D. in war zone soldiers may be responsible for the increased inflammatory reactions in the active duty American soldiers. Mast cells could play an important role in the battlefield soldiers due to stress, mood, fearful behavioral activities, and change in the outer environmental conditions. Mast cell numbers are high in the skin, gastrointestinal tract, and respiratory tract through which the body is directly exposed to outer environment. Changes in the outer environmental conditions such as outside temperature (cold or hot), light and darkness, odors, and toxic substances in the air affects/activates mast cells in the barrier regions and increases their numbers to respond. For example, outer environmental cold and low humidity conditions activate skin mast cells, allergen/toxins in the air activates nasal, airways, and ocular regions mast cells and causes acute or chronic allergic and inflammatory reactions. Additionally, human behavioral and emotional conditions also influence mast cell activations and their numbers in specific regions of the body including in the brain areas.

A previous report suggests that P.T.S.D.-like trauma with high C.R.H. level induces dementia and A.D. pathogenesis. Studies have linked P.T.S.D. with inflammation related diseases, elevated inflammatory responses, and accelerated aging process. Peripheral inflammatory markers and total inflammatory scores are shown to be higher in combat experienced veterans with P.T.S.D., as compared to veterans without P.T.S.D. It is interesting to note that comorbidity of T.B.I. and P.T.S.D. shows augmented inflammation, associated with elevated I.L.-6 and T.N.F.- alpha levels, and this increase correlates with the severity of P.T.S.D. symptoms. Similarly, studies have also shown elevated levels of I.L.-6, I.L.-1 beta , T.N.F.- alpha , and I.F.N.- gamma in P.T.S.D. patients. These cytokines can bind to receptors in the glial cells and phosphorylate M.A.P.K.'s, which leads to the activation of nuclear factor-kappa B N.F.- kappa B) and release of inflammatory mediators. Supporting this notion, we have previously reported that I.L.-1 activates mast cells to release I.L.-6 through the activation of p.38 M.A.P.K. A recent report indicates that chronic stress and anxiety increases the rate of P.T.S.D. Systemic inflammation marker, C.R.P. is increased in depression as well as in P.T.S.D. patients, indicating that P.T.S.D. patients show enhanced inflammatory responses. Thus, it has been suggested that certain inflammatory markers can be used as biomarkers for P.T.S.D.

A study conducted on Iraq and Afghanistan deployed U.S.-veterans under the age of 55 that were associated with P.S.T.D. and endocrine and immune abnormalities reported increased risk for developing autoimmune diseases such as M.S., rheumatoid arthritis, thyroiditis, lupus erythematosus, and inflammatory bowel disease (I.B.D.). Hence, there is a clear evidence that P.T.S.D. is an important risk factor for several autoimmune and mast cell associated diseases. Cytokines and chemokines including T.N.F.- alpha , I.L.-6, and I.L.-1 beta cross B.B.B. and induce neuroinflammation directly, and also by activating inflammatory, glial, and neuronal cells in the brain (Banks et al., 1995). Further, inflammatory cytokines released from activated glial cells, and inflammatory cells contribute to the chronic pain in P.S.T.D. (Lerman et al., 2016). Additionally, mast cell-derived inflammatory mediators including S.P. strongly contribute to the pain in P.T.S.D. patients. Stress increases the release of C.R.H. and this C.R.H. activates H.P.A. axis in stress responses in P.T.S.D. patients with depression (Mendoza et al., 2016). This elevated C.R.H. increases the vascular permeability and activates glial cells and inflammatory cells such as mast cells to release additional inflammatory mediators (Mendoza et al., 2016). Moreover, mast cells also contribute to the increased level of C.R.H. in the brain, as mast cells are target as well as source for C.R.H. as we reported previously. During the stress conditions, elevated inflammatory mediators cross B.B.B. and induce/augment neuroinflammation that accelerates the pathogenesis of A.D. These findings indicate that stress accompanied with chronic inflammation in P.T.S.D. could lead to neurodegeneration in diseases such as A.D. Moreover, P.T.S.D. is a known risk factor for dementia in the veterans and also in civilians (Flatt et al., 2017). However, mast cells are clearly involved in peripheral and C.N.S. inflammation and in various stress conditions and trauma, but the exact role of mast cells is not yet studied in P.T.S.D. patients. Moreover, mast cells could increase both acute and chronic inflammatory reactions in stress, brain injuries, and P.T.S.D. and could contribute to the development and progression of A.D. (Figure 1).

Mast Cells, Neuroinflammation, and A.D.

A.D. is the most prevalent chronic progressive neurodegenerative disease associated with dementia, neuroinflammation, and neurodegeneration. A.D. is considered as an inflammatory disease involving immune components in the brain. A.D. pathogenesis begins even 10 years before the clinical symptoms are identified in A.D. patients. There are no effective drugs to treat neurodegeneration in A.D. since the disease mechanisms are not yet clearly understood. Anti-inflammatory and antidepressants can reduce neuroinflammation in dementia and A.D. Inflammatory mediators induce neuroinflammation, synaptic dysfunction, hyperphosphorylated tau generation, Aβ production, and neurodegeneration in the brain. Anti-inflammatory drugs are neuroprotective and suppress disease progression by reducing Aβ generation and its accumulation, inflammatory mediator release with improvement of cognitive functions (Budni et al., 2016;

McGeer et al., Mohammadzadeh Honarvar et al., Aβ pathology and normal aging processes are associated with activation of immune as well as inflammatory cells in the brain. Neuroinflammation and neurodegeneration are vicious cyclic processes in neurodegenerative diseases and in normal aging processes. Available current research evidence indicates that neuroinflammation clearly contributes to the neurodegeneration in several neurodegenerative diseases. However, the exact mechanism of neuroinflammation is not yet clearly understood.

Neuroinflammation is a complex mechanism involving different immune and inflammatory cells and different inflammatory mediators in A.D. pathogenesis, brain injuries, and stress conditions. The currently available anti-inflammatory drugs are not affecting all or the key inflammatory mediators or genes in these conditions. Moreover, these diseases and disorders are multifactorial and the anti-inflammatory drugs or antidepressants need to affect specific inflammatory pathways and inflammatory mediators in specific diseases for its maximal beneficial effects.

B.B.B. is one of the main problems in delivering the drugs that acts on neuroinflammation. These drugs should also be effective in stress-mediated hormonal disorders in addition to neuroinflammation. C.R.H.-antagonists could be therapeutic agents in stress-related C.N.S. and peripheral inflammatory disorders. More importantly, anti-inflammatory and other currently available drugs do not completely stop the onset or progression of the disease and do not induce regeneration of neurons and its network connections in the affected brain regions. Continued and extensive research in this field is essential to achieve this goal in the future.

Definition

Glia maturation factor (GMF): A brain proinflammatory protein involved in the pathogenesis of AD and MS/EAE. It regulates neuroinflammation through the NLRP3 inflammasome in the AD brain, and is expressed by mast cells.

Various conditions including stress conditions induce/augment neuroinflammation and A.D. pathogenesis. Mast cell activation causes either neuroprotection or neuroinflammation based upon the level and number of cells activated. Excessive and chronic activation of mast cells lead to neuroinflammation and neurodegeneration. Though mast cells are implicated in neuroinflammatory diseases such as M.S., E.A.E. and P.D., the role of mast cells in A.D. pathogenesis is still elusive. Several lines of evidence indicates that mast cell activation could accelerate A.D. pathogenesis in high-risk group patients with brain injury and trauma, stress conditions, and P.T.S.D. Since mast cells play important role in inflammation, neuroinflammation, stress, and psychiatric disorders, it is important to study its role in the pathogenesis of P.T.S.D.-associated neurodegenerative diseases such as A.D. Several recent studies show that proinflammatory cytokines and mast cell-derived inflammatory mediators are implicated in neuroinflammation and neurodegeneration in the C.N.S. Brain proinflammatory protein glia maturation factor (G.M.F.) which was discovered in our laboratory is involved in the pathogenesis of A.D. and M.S./E.A.E. We have recently reported that G.M.F. regulates neuroinflammation through N.L.R.P. 3 inflammasome in A.D. brain. Further, we have shown that mast cells also express G.M.F. and suggest that G.M.F. in mast cells may also play an important role in the pathogenesis of neurodegenerative diseases including A.D. Additionally, we have also shown that G.M.F. activates mouse and human mast cells to release mast cell specific proteases and other neuroinflammatory mediators that are implicated in neuroinflammation and neurodegeneration in P.D. and A.D. We have previously reported enhanced expression of I.L.-33 and G.M.F. at the vicinity of A.P.'s and N.F.T.'s in human A.D. brain. Further, we demonstrated that incubation of mouse astrocytes with Aβ 1 to 42 in vitro increased the expression of I.L.-33 indicating I.L.-33 is implicated in A.D.

S.P. is involved in the neurodegenerative diseases. We have shown that I.L.-33 increases S.P.-mediated release of inflammatory mediator from mast cells. These results suggest that I.L.-33 released from astrocytes could activate microglia and mast cells in the brain, as I.L.-33 is a strong activator of mast cells. However, another study showed that injection of I.L.-33 led to improved memory deficit in A.P.P./P.S. 1 A.D. mice model. This suggests that I.L.-33 could act differently depending upon the environment and concentration. Mast cells are the first immune responding cells in the brain before other cells in certain conditions. Mast cells are suggested as one of the first brain cells that detect and respond early to Aβ formation in the pathogenesis of A.D. These studies suggest that mast cells specifically identify the ongoing process in the formation of Aβ in the pathogenesis of A.D. The association of mast cells and A.D. is reported in mastocytosis (increased mast cells in the body) patients. Expression of Aβ peptide, major component of amyloid plaques (A.P.'s) in A.D. and tau-protein has been reported in the skin mast cells of mastocytosis patients. Aβ peptide has been reported to activate mast cells to release inflammatory mediators that are implicated in the pathogenesis of A.D. Increased levels of R.O.S. in A.D. could activate mast cells to release inflammatory mediators. Several mast cell-derived inflammatory mediators are reported to be involved in the A.D. pathogenesis and its level of severity. Mast cells, in fact, are similar to neurons with regard to synthesis and secretion of neurotrophic factors, responsiveness to neuropeptides and monoaminergic content such as dopamine.

Mast cells are mostly located in choroid plexus, leptomeninges, and brain parenchyma and form a unit in the neurovascular structure in the C.N.S. Mast cells migrate and accumulate in the specific region of the brain. Many factors such as cytokines/chemokines, eicosanoids, V.E.G.F., and fibroblast growth factor F.G.F., platelet-derived endothelial cell growth factor influence the movement, activation and degranulation of mouse mast cells. Several neurotrophic factors induce mast cells to release histamine that activates microglia through histamine receptors H.1. and H.4. to release neurotoxic mediators such as I.L.-1beta, T.N.F.-α, I.L.-6, and nitric oxide (No). These proinflammatory mediators directly induce neuronal death in the brain. Inflammatory cytokines such as I.L.-1beta are known to phosphorylate tau and induce neurodegeneration. Aβ-peptides are normal products of the metabolism that induce localized as well as general inflammatory responses [10]. Elevated intracellular concentration of calcium induces Aβ aggregation in the A.D. brain and activates human mast cells to release inflammatory mediators. The number of mast cells in the normal brain is less; however, the number increases in the affected regions in A.D. brains.

Mitochondrial uncoupling proteins U.C.P.'s are implicated in neurodegenerative diseases. We have recently reported downregulation of the expression of U.C.P.'s 2 and 4 in the parahippocampal gyrus of A.D. brains where G.M.F. expression is also increased. We have also previously shown that mast cells express U.C.P. 2 and U.C.P. 4 (Tagen et al., 2009; Kempuraj et al., 2016a) and G.M.F. Further, we showed that deficiency of U.C.P. 2 in mouse mast cells decreased the release of inflammatory mediators such as I.L.-6, P.G.D. sub 2 , and histamine with inhibition of M.A.P.K.'s activation. Another study has shown that U.C.P. 2 deficient microglia released more No and I.L.-6 when stimulated with lipopolysaccharide. These findings show that mast cell U.C.P.'s could be implicated in the pathogenesis of A.D.

Although recent reports suggest that mast cells and C.R.H. are crucial in the pathogenesis of A.D., there are some controversies regarding this hypothesis. The concentration of C.R.H. has been reported to be higher in the regions prone to develop A.D. related pathological changes. Mast cell activation induces postoperative cognitive dysfunction P.O.C.D. after surgical procedure-mediated neuroinflammation. Chymotrypsin-like protease was reported in the meningeal and intracortical perivasculature where there is high Aβ accumulation in rat A.D. brains. This chymotrypsin-like protease has been suggested to influence aggregation of Aβ deposition. Mast cells express IgE receptor F.c.epsilon.R.I., release histamine and play important role in mediating various allergic reactions. Presence of allergic diseases such as asthma in which mast cells are increased as well as heavily activated are strongly linked to phosphorylation of tau, dementia, and A.D. We have recently reported that mast cell activation in several inflammatory conditions in the periphery could increase neuroinflammation and neurodegeneration. These findings show that mast cells are implicated in the pathogenesis of A.D. Moreover, it has been shown that mast cells play important role in stress induced severity of asthma. Stress conditions exacerbate asthma severity by increasing the number of mast cells as well as increased number of activated mast cells.

Conclusions and Perspectives

Mast cell activation is implicated in neuroinflammation, brain injuries, and various stress conditions. We suggest that mast cells participate in the pathogenesis of A.D., and this process could be accelerated and worsened in brain injury, stress, and P.T.S.D. comorbidity. Inhibition of mast cell-associated inflammatory pathways in brain injury, stress, and P.T.S.D. could be explored as a new therapeutic target to inhibit or prevent the pathogenesis and potentially delay the onset of A.D. Though the evidence is currently limited, investigating the role of mast cell activation in brain injuries, stress, and P.T.S.D. comorbidity in the onset and progression of A.D. is an important emerging new area to understand and to effectively treat neuroinflammatory disorders including A.D.

Author Contributions

D.K.: Conceptualization, wrote, and edited the manuscript; A.Z.: Funding acquisition, provided resources and edited the manuscript; G.S., R.T., M.A., S.Z., S.R., S.I., S.B., and S.B.-R: Edited the manuscript.

Funding

This work was supported by the National Institutes of Health Grants # A.G.048205, # N.S.073670, and Veteran Affairs Merit Award # I.01.B.X.002477 to A.Z.

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